In This Chapter
Identifying what families and friends need to know about research
Examining new approaches to drug discovery and newly emerging technologies
Looking into the brain
Finding out about complementary and alternative treatments for schizophrenia
Determining whether participating in a clinical trial is right for your loved one
Keeping abreast of new research on the Internet
Almost every day, there’s a news report on television, on the radio,or in a newspaper or magazine announcing some fantastic new health breakthrough. These breakthroughs sound so promising that consumers often rush to their doctor for the “latest treatment,” only to find out that the marvelous results reported are from preliminary studies, conducted with small numbers of people, and that they haven’t been verified by other researchers. It may be years before the reported treatments or drugs are available to the general public. Yet, if your loved one is suffering from a disorder such as schizophrenia, these reports provide a glimmer of hope for the future. In fact, some of these reports turn out to herald real advances.
Although having all the answers necessary to prevent and cure schizophrenia would be wonderful, research is generally a slow, incremental process, where one scientist’s findings build upon another’s. Clinical trials take considerable time to complete, and many don’t live up to their original promise.
In this chapter, we look at the most current research on treatments for schizophrenia — its promises and pitfalls. We also answer the question of why new drugs take so long to get into pharmacies and how doctors know that certain drugs work. Finally, we take you behind the scenes of research, giving you insight into how clinical trials are done, and help you decide whether your loved one should participate in a clinical trial.
Understanding the Process of Research
Research is technically defined as “the systematic collection of data which is intended to be used beyond the place where it is collected.” Without continued research, medical knowledge would stagnate. Early medical advances sometimes involved accidental discoveries of new medications or treatments, but today’s advances are more likely to be the result of years of medical research. And research today is generally no accident.
Although much has been learned about diseases of the brain over the last few decades, leading to improved treatment, care, and quality of life, much more remains to be learned. Fortunately, a growing number of interdisciplinary researchers (in psychiatry, biology, chemistry, neuroscience, psychology, and medicine) are working diligently to answer the still unanswered questions about the causes of schizophrenia, with an eye toward prevention, early intervention, and better treatment and services. Because they share these same goals, people with schizophrenia, their friends and family members, and mental-health professionals have led the charge for increased research.
Aside from the human costs, the financial costs of mental illness in the United States are estimated at more than $150 billion annually, with the largest portion of that cost due to the lost productivity associated with mental disorders. Yet, research on mental illness has traditionally been underfunded compared to research on chronic physical problems like cancer, diabetes, and heart disease. This is due, in no small part, to the social stigma associated with schizophrenia.
The 2008 funding for the National Institute of Mental Health (NIMH) was about $1.4 billion, an increase of about 0.1 percent over the year before. This marks the fifth consecutive year that the NIMH budget grew at a rate less than biomedical research inflation, which is estimated at 3.5 percent per year. This makes for a highly competitive research environment, with many research projects competing for the same funding.
Recently, there has been a greater emphasis on the importance of translational research, which takes findings from the laboratory bench to the proverbial bedside. This research is conducted at the basic laboratory level with the clear expectation that it will be applied to a clinically relevant problem. For example, instead of studying hearing for its own sake, investigators focus their work on the role of hearing in relation to the auditory hallucinations prominent in schizophrenia.
Making sense of the mental-health research enterprise: The major players
A number of public and private sources support mental-health research. One of the most important is the National Institute of Mental Health (NIMH): At the federal level, the NIMH, a part of the National Institutes of Health (NIH), is the focal point for the funding of mental-health research on brain, mind, and behavior — ranging from basic science to clinical practice.
With overall funding caps and growing inflation, NIMH is expected to place greater emphasis on funding schizophrenia research, particularly around the first signs of the illness before diagnosis, around genetics, and around cognitive deficits (see Chapter 3).
NIH maintains a search engine called CRISP (www.crisp.cit.nih.gov) that enables anyone to look at the current portfolio of mental-health research grants funded by the federal government.
Other important players in mental-health research include
The Substance Abuse and Mental Health Services Administration (SAMHSA):
SAMHSA, which includes the Center for Mental Health Services (CMHS), funds studies on the implementation, cost, and effectiveness of mental-health and substance-abuse services. The agency has led the charge in pioneering studies of peer and consumer-run services, identification and treatment of co-occurring mental-health and substance-abuse disorders, and mental-health initiatives focused on special populations.
The Agency for Healthcare Research and Quality (AHRQ): AHRQ focuses on developing information tools to assist health
(including mental health) policymakers to improve the way care is organized, financed, paid for, and regulated.
National Alliance for Research on Schizophrenia and Depression (NARSAD): The donor-supported NARSAD is the world’s leading charity dedicated to mental-health research. As of March 2008, NARSAD has awarded a total of $219 million through 3,243 research grants to scientists in 418 institutions in the United States and 26 other countries. The organization raises and distributes funding for promising psychiatric research in order to develop new preventive measures, better diagnoses, and improved treatments for these conditions. NARSAD also educates the public about the value of psychiatric research.
NARSAD recently collaborated with the NIMH to create the Schizophrenia Research Forum(www.schizophreniaforum. org), a unique online resource for scientists and the public. One portion of the site highlights new and significant research findings.
Other private foundations: The Stanley Research Foundation, the Robert Wood Johnson Foundation, the van Ameringen Foundation, the John D. and Catherine T. MacArthur Foundation, and many others are instrumental in funding psychiatric research. Additionally, private industry, particularly pharmaceutical and biotechnology companies, provide funding support for additional studies of new compounds, drugs, devices, and technologies.
Looking at Clinical Trials and How They Work
Much of what is known in medicine, including which medications work best, is determined by medical research done through clinical trials (experimental studies designed to determine whether there is a cause-and-effect relationship between an intervention (treatment) and an outcome (symptom) — for example, is a drug effective in controlling positive symptoms of schizophrenia?). Controlled clinical trials are considered the gold standard for research. In these studies, the new treatment (called an intervention) is compared to an ineffective treatment or to an already existing treatment in a fair, unbiased way.
Seeing how clinical trials are conducted
In a controlled clinical trial, one group of people (called the experimental group) is given a drug, and another group of people (called the control group) is given a placebo (an inert substance, like a sugar pill) or a known standard medication. The investigator (the person conducting the research) compares the effects seen in these two groups. If there’s a statistically significant difference (a difference not likely to be due to chance) between the two groups in terms of reducing the symptoms (called the outcome measure), the medication is determined to be effective.
Each person going into the trial has an equal chance of getting the active medication or the placebo; this is known as randomization. By assigning people to the different treatment groups randomly, it’s more likely that the groups will be equal and that any differences seen will be due to the treatments they receive. Another way of preventing bias in a trial is called double-blinding. This means that neither the person receiving the medication nor the person evaluating the response knows whether an active or inactive medication has been given. If they did know, they might unintentionally be more enthusiastic if they knew they were receiving or judging the active rather than the inactive medication.
In some circumstances, experimental research can’t be conducted. For example, a researcher wouldn’t give an ill person a drug that makes his condition permanently worse. So in cases like this, researchers use correlational methods, which look at the relationships between two variables to see if they’re related. Correlational methods are unable to definitively establish cause and effect.
In the case of medications, the first clinical trials (called Phase I trials) are conducted using healthy volunteers, to make sure the drug has no serious side effects.
Clinical trials are easier to evaluate when interventions or outcomes can be precisely measured. Some clinical trials related to schizophrenia test psychosocial approaches. Although the principles of experimental design are similar, it’s more difficult to accurately measure the dose, quality, or purity of a complex psychosocial intervention as compared to measuring, for example, the dose of a medication.
No one study, however well designed and executed it may be, is ever considered as absolute proof that something is beneficial. Studies are repeated by other investigators to be sure they get the same results and that the findings are reliable.
Evidence-based treatment is a term often used to identify interventions that have been tested and have been proven effective. In the case of medications, the Food and Drug Administration (FDA) must find the treatment safe and effective and that the benefits of the medication outweigh its risks before the drug can be sold.
Deciding whether to participate in clinical trials
In all areas of medical science, clinical research depends on the participation of volunteers. If your loved one with schizophrenia doesn’t respond to various existing treatments, her doctor may suggest that she consider enrolling in a clinical trial that will compare a promising new treatment (which may not be available elsewhere) to one or more treatments that are already used and approved. Being asked to participate in a clinical trial can be both exciting and a little frightening.
People participate in clinical trials for a variety of reasons, including the following:
To advance science and help save lives
To take advantage of new treatments and be at the forefront of therapeutic breakthroughs
To try something different when their illness is treatment-resistant
To receive high-quality medical care with close monitoring for little or no cost
At the conclusion of a study, researchers have a responsibility to disseminate their findings to other researchers, clinicians, the general public, and to policymakers.
What is informed consent?
informed consent refers to the process of fully explaining to the person participating in research what the study entails, including potential benefits and risks, and then obtaining her voluntary agreement (or consent).
Informed consent is so important in research that no human participants can be involved in any way until after informed consent has been obtained. Informed consent presents special problems when subjects may not be deemed legally capable of understanding what’s involved with a study. But having a mental disorder doesn’t necessarily mean that a person is unable to understand or evaluate the benefits and risks of participating in clinical research. Many people with schizophrenia can provide informed consent.
When an individual is not able to provide informed consent because she lacks the capacity to understand the proposed research, she often has the capacity to name a surrogate or substitute who can make the decision for her. Safeguards exist so that consent is obtained both from the participant and a legally authorized representative, such as a parent, a guardian, or a spouse.
Deciding whether to participate in a clinical trial requires some thought and investigation. When your loved one is considering whether participating in a clinical trial makes sense, here are some things you’ll want to do:
Using the Internet or visiting the library, find out whatever information you can about the available treatments for your loved one’s condition. The National Library of Medicine (NLM; www.nlm.nih.gov) provides current information on various conditions and their treatment. You may also be able to get information from some of the mental-health research and advocacy organizations we list in the appendix. The more you learn, the better prepare you’ll be to ask questions about the trial and what it can do for your loved one.
Discuss treatment options with your loved one’s psychiatrist or another health professional whom you know and trust. They can help you weigh the respective risks, outcomes, and benefits of participation in a trial.
Involve a trusted friend or family member in the decision. Bring them with you when you go to learn about the trial. They may hear things you don’t hear or see things differently.
Most clinical trials cover the cost of evaluation, treatment, and transportation. What is paid for and what is not should be spelled out in the informed consent form (see the nearby sidebar, “What is informed consent?”). The study director will also help your loved one transition into some appropriate type of follow-up care after your participation in the study is completed.
Finding the right trial for your loved one
Sometimes your doctor will know about a trial going on that may be just right for your situation. But don’t be limited by recommendations from one doctor or a particular institution that advertises in the newspaper or on the radio. Here are some tips for finding the right trial for your loved one with schizophrenia:
Find out the trials for which your loved one may be eligible. The National Institutes of Health (NIH) maintains a registry of clinical trials (www.clinicaltrials.gov) to provide patients and family members with information about governmental and privately sponsored trials. The site includes general information about each trial’s purpose, who may participate, location, and a phone number to call for more information.
The information at www.clinicaltrials.gov is intended to be used in conjunction with advice from healthcare professionals.
Eligibility for clinical trials is usually based on very specific study criteria. For example, your loved one may be too old or too young, have other complicating emotional problems, or have health problems that preclude participation. Don’t take rejection personally. Instead, recognize that it’s intended to protect your loved one and make sure that the trial provides the precise answers for which it is designed.
Speak to the study director or other investigators at the site. If your loved one participates in a trial, the research will likely be conducted at a physician’s office, clinic, hospital, or other healthcare setting. Be sure to meet with the staff at the site beforehand so you and your loved one feel comfortable there and understand the procedures.
Learn about the process of informed consent. Carefully read the informed consent form that outlines key facts about the clinical trial — including procedures, risks, benefits, and expected outcomes. The form should be user-friendly and easy to read. If it isn’t, be sure to ask questions. Even after enrollment, you have the right to raise any concerns you have with the director of the study or the director of the institutional review board (IRB; see the sidebar “Institutional review boards: They’ve got your back,” in this chapter).
Informed consent is not a one-time event but a continuing process. You also have the right to withdraw from a study at any time for any reason.
Although participating in a clinical trial may not be the right choice for every person, every condition, or in every situation, it does offer possible benefits for some patients — and trials provide information and hope for others who will benefit from the results.
An institutional review board (IRB) is a committee established under federal and state regulations to protect the rights and welfare of people who participate in research. IRBs review all proposed research involving human subjects. They approve only studies that meet strict criteria for the protection of people who participate in them. IRBs are comprised of health professionals, scientists, lay people, consumers, family members, community members, quality assurance representatives, statisticians, and ethicists; this broad range of expertise allows the IRB to consider the burdens potentially placed on participants.
If you’re participating in a trial being conducted by a hospital or other large institution, that institution may have its own internal IRB that reviews and approves all their clinical trials. Studies done through physicians’ offices are overseen by a central IRB, which looks at research done at a number of different clinical sites.
Any IRB, whether specific to an institution or centralized, looks to make sure safeguards are in place to protect participants. When research studies are discussed, approval is made only if the following criteria are met:
Risks to subjects are minimized.
Risks are reasonable in relation to anticipated benefits.
Selection of subjects is equitable.
Informed consent will be sought and documented from each subject or the subject’s legally authorized representative.
Appropriate monitoring will take place.
Adequate provisions will be in place to protect the privacy of individuals and the confidentiality of their data.
Useful information will likely result from the study.
Many family members volunteer to participate as healthy volunteers in non-interventional studies where they may have MRIs taken or provide blood for genetic studies. This is one way friends or family members of persons with schizophrenia can help advance research on their loved ones’ illnesses.
New and Promising Directions in Research
There has never been a more exciting or productive time in the history of schizophrenia research than the present. New techniques in the basic sciences (molecular biology and genetics) have allowed scientists to better study the neurobiology of the brain and its relationship to schizophrenia.
Institutional review boards: They’ve got your back
New pharmacologic and clinical imaging techniques allow scientists to study the brain as well as follow the course of the disorder and examine the impact of treatment.
More attention is being focused on public attitudes and the harmful effects of the negative stigma associated with schizophrenia, and on the importance of both peer support and recovery (see Chapter 15). Psychosocial treatment and health services research is aimed at studying a broad range of interventions to improve functioning and quality of life, as well as the best ways to deliver these treatments (see Chapters 9 and 15).
So, with all this research and discovery, why don’t scientists yet have all the answers? Simply put, this type of complex, biopsychosocial research (research that combines biological, psychological, and social approaches) does not progress in a simple straight line from point A to point B, like constructing a building from a plan. It’s more like painting a picture, where each scientific article is a little dab of paint on a different part of the canvas. We can’t recognize the picture until enough paint has filled up the blank spots on the portrait. Sometimes we can’t even be sure of what is background and what is foreground without repeating studies and determining their relevance to the other dabs of color on the canvas.
In the following sections, we fill you in on new drugs and other treatments and technologies that are on the horizon, which may prove successful in treating schizophrenia.
New directions in drug discovery
One area of development involves the creation of new classes of medications — which may work along with the current antipsychotics or possibly one day replace them.
Current antipsychotic medications are good at controlling the positive symptoms (hallucinations, delusions, and agitation) seen in schizophrenia. Because they’re so good, we’ve come to recognize that, after the positive symptoms clear, people with schizophrenia still have underlying and very profound problems with cognition (memory, verbal ability, decision-making) and so-called negative symptoms (such as lack of motivation, problems socializing, and the inability to experience pleasure).
Very precise neuropsychological tests have been developed that can measure cognitive performance in people with schizophrenia. Not only have deficits been noted, but some deterioration in cognitive abilities has been found even before these individuals were diagnosed with schizophrenia. And perhaps even more important, the severity of cognitive impairment has been found to be related to the person’s inability to function even after their positive symptoms are treated with antipsychotic medications.
Therefore, a great deal of focused effort is now underway to develop medications that specifically target the cognitive impairments of schizophrenia. Because antipsychotic medications are thought to work primarily by blocking dopamine receptors in the brain and these medications control positive symptoms, researchers are searching for medications that will affect other neurotransmitters and correct or lessen cognitive deficits.
In the following sections, we cover three new approaches that offer hope for treating some of the cognitive symptoms of schizophrenia that have long eluded prior therapeutic efforts.
Although it’s somewhat hard to understand how all these different systems in the brain could be responsible for some of the symptoms of schizophrenia, these systems are linked to one another. If researchers can identify and correct the crucial malfunctioning system, the other “upstream” and/or “downstream” systems may also be corrected with significant therapeutic benefit.
Glutaminergic approaches
One clue about what system to study came about by the clinical observation that phencyclidine (PCP, commonly called angel dust), a drug of abuse, causes a variety of symptoms (including cognitive deficits) that look like schizophrenia. Using this drug, pharmacologists and biochemists were able to show that it had the effect of blocking a receptor in the brain (called NMDA), which was stimulated by the neurotransmitter glutamine.
Drugs other than PCP, which also block glutamine neurotransmission, were found to cause cognitive problems, too. Glutamine receptors are found widely distributed in the brain, and the glutamate system interacts with the dopamine system (as well as other neurotransmitters systems — for example, GABA).
With this understanding — in other words, that blocking glutamate receptors causes cognitive problems — the hypothesis emerged that cognitive problems in schizophrenia may be due to insufficient glutamine activity in the brain. In order to test this hypothesis (and see whether increasing or stimulating glutaminergic activity could reverse cognitive problems), a search has begun for medications that may have this biological effect.
Currently three substances that are relatively simple amino acids (glycine, serine, and sarcosine), all of which increase glutaminergic transmission, have been studied both in the laboratory and in human clinical trials. Some small clinical trials have had relatively positive results, but the largest trial using glycine called into question the effectiveness and practicality of using it as a treatment. In order to be effective, glycine has to be given in large quantities
(usually as a citrus-like drink), and this has been found to be too difficult for many patients to tolerate and has caused to some gastrointestinal side effects. Studies with serine are ongoing in the United States and Israel, but sarcosine is not currently approved for study in the United States.
With this foundation, ways of facilitating glutaminergic transmission other than using the amino acid approach are underway. One fairly large clinical trial has been reported by Eli Lilly and Company using a metabotropic (a different type of receptor function) glutamate approach that reportedly affects both positive and cognitive symptoms favorably. Other companies are using so-called glutamine transporter inhibitor compounds to enhance glutaminergic transmission, but clinical results have not yet been reported.
So, although there is great research activity and drug discovery effort pointed in new directions, there hasn’t yet been any proven success, either in terms of efficacy (producing a desired effect) or safety, in developing a new class of cognition-restoring or cognition-enhancing medications based on facilitating glutaminergic function.
Noradrenergic approaches
A second approach to treating cognitive deficits in schizophrenia is related to the noradrenergic neurotransmitter receptor system located specifically in the prefrontal cortex of the brain, which is known to be important for cognition. Studies of humans with schizophrenia and memory/cognition studies of animals both show the association of this system with some of the cognitive deficits found in people with schizophrenia.
Two types of medications have potential for correcting these deficits. One is called an alpha 2a selective agonist, and a medication with this activity named guanfacine has actually been tried as an add-on treatment in persons already receiving second-generation antipsychotics (see Chapter 8). Improvements in both memory and reaction time were noted in preliminary studies, but confirmatory studies need to be carried out over longer periods of time to see if meaningful clinical improvement is seen.
The other approach to correcting noradrenergic problems is with the use of so-called specific norepinephrine reuptake inhibitors. Medications with this activity (for example, atomoxetine [brand name, Strattera]) are already in use to treat attention deficit/hyperactivity disorder (ADHD). Results of controlled clinical trials testing this therapeutic possibility have not yet been reported.
Cholinergic approaches
The cholinergic system is another system that plays an important role in relation to cognitive functioning. Its major neurotransmitter is called acetylcholine, and it attaches to a nicotinic receptor and a so-called muscar-inic receptor. Both types of receptors have been shown to be implicated in neurophysiologic malfunctions in some people with schizophrenia.
Some 80 percent of people with schizophrenia are heavy smokers, and it’s thought that the nicotine in cigarettes may actually reverse some of the neurophysiological (nervous system) deficits associated with schizophrenia. It’s been suggested that medications that directly stimulate these receptors — so-called nicotinic agonists — might be useful therapeutic agents. However, so far there are no significant clinical trial results available.
Other new technologies
Recent advances in technology have led to the development of new techniques that once could never have even been imagined. Two such techniques that are currently being studied in multiple sites include deep brain stimulation and repetitive transcranial magnetic stimulation.
Deep brain stimulation
Deep brain stimulation (DBS) — which sounds a little like science-fiction — involves implanting a battery-powered, high-frequency pulse generator, either in the region of the collarbone or in the abdomen, and running a wire under the skin up the neck, behind the ear, and to the head. Tiny electrodes are placed at specific sites in the brain, and electrical signals are sent to interfere with brain activity at these preselected sites. The type and strength of pulses sent can be varied by a computer controlling the battery-operated stimulator.
DBS was developed and has been proven useful for treating various types of movement disorders (such as Parkinson’s disease); in fact, it’s estimated that some 35,000 people around the world have had DBS electrodes placed. Its use for the treatment of mental disorders is at a very preliminary stage — more studies have been done on the effects of DBS on depression and obsessive-compulsive disorder than on schizophrenia.
Repetitive transcranial magnetic stimulation
Transcranial magnetic stimulation (TMS) is a noninvasive way to cause an electrical activation of the brain, using a magnetic field (which easily passes through the skull). This electromagnetic stimulation can be precisely varied in its strength, location, duration, and frequency and is a tool for studying the brain and as well as a potential treatment.
Repetitive transcranial magnetic stimulation (rTMS) is the use of grouped pulses of stimulation, which causes a continuous activation over brief periods (minutes) of a treatment session. rTMS has been more intensely studied as a treatment for depression, but a number of experimental treatment studies have been carried out in people with schizophrenia.
Attempts have been made to use rTMS to treat both the positive and negative symptoms of schizophrenia. People with persistent treatment-resistant auditory hallucinations have had the hallucinations markedly reduced in some studies, but this improvement has not been lasting, and no follow-up studies have been conducted. Some studies have not shown beneficial effects, but these differences may be accounted for by both patient differences and differences in the way the rTMS was administered (for example, duration and frequency).
Studies attempting to treat negative symptoms have also shown mixed success. Different frequencies of stimulation at a different location (in the prefrontal cortex) from the auditory hallucinations studies were used. The most promising results seem to occur when the frequency of stimulation used is matched to the alpha (brain wave) frequency seen in each individual, rather than just using the same frequency for everyone.
In general, then, rTMS looks like a potentially promising noninvasive treatment, but the correct “dosing” (duration, frequency, location) is not well enough studied or understood to consider it a viable treatment alternative.
Opening New Windows into the Brain
Opportunities to study the brain, especially the living brain, have increased dramatically over the past 35 years. Before the advent of newer imaging techniques — such as magnetic resonance image (MRI) and positron emission tomography (PET) — the ways to directly study the brain were limited. These included X-rays and brain biopsies (removing a piece of brain during neurosurgery).
Surgically placing electrodes in the brain permitted direct examination of the electrical functioning of the living brain. Indirect measures such as electrical recordings from the scalp (called EEG and evoked potentials) and measuring chemicals in the spinal fluid that bathes the brain were other techniques that were used with some success. Postmortem studies of the brain could be carried out, but brain composition changes with death and no measurement of ongoing mind function was possible.
With the discovery and refinement of MRI, however, it became possible, without touching the brain directly, to image the structure (the physical configuration), the function (activity), and the composition (chemistry) of the brain. No radioactivity is involved — only magnetism — so imaging can be done as often as necessary with no physical risk to the person being imaged.
You may also hear an MRI referred to as an fMRI (short for functional MRI) and MRS (the S stands for spectroscopy) studies.
PET imaging and a related technique known as single photon emission computed tomography (SPECT) were also developed about 35 years ago. Both of these techniques require the administration of a small amount of a radioactive substance to the person being imaged. Although very useful for studies of brain receptors and specific drug actions, frequently repeated examinations using this technique are not possible because of the radioactivity involved. Nonetheless, PET and SPECT give rise to some types of information not available through MRI study. Thus, MRI and PET are considered complementary imaging methods.
Both MRI and fMRI studies have shown differences in the structure and function of the brain between groups of people with and without schizophrenia. These differences have pointed at areas and functions where something has gone wrong.
No new treatments, either biological or psychological, have yet directly resulted from MRI studies. But imaging has been important in learning more about schizophrenia and the brain, and it offers hope for the future. By investigating the biology of what has gone wrong, researchers are likely to find ways to “fix” the broken areas.
Another potential use for MRI is to help test whether treatments are actually having an effect. If scientists know that one area of the brain in people with schizophrenia has to work harder to solve a cognitive task and they give the person a medication, they can use the MRI to see if the brain doesn’t have to work as hard to solve that task with medication. (The technology may actually be able to see improvement in brain function prior to any changes in the behavior of the person.) If the medication doesn’t work on the brain function, then researchers don’t need to conduct long and expensive clinical trials. Testing in this way is sometimes called proof of concept.
Another way to use the MRI to study the brain is a technique called diffusion tensor imaging (DTI). With this method, we can see the white matter of the brain and know whether it’s intact or damaged. In the brains of people with schizophrenia, white matter pathways that connect different areas of the brain have been found to be damaged. This means that vital communication between one part of the brain and another, which must be closely synchronized to function appropriately may be out of sync — something like what you experience when the sound and picture of someone talking on TV or in the movies doesn’t match. Imagine if that happened to your thinking!
Very precise studies, presenting sounds (tones of differing pitches) and pictures (with areas missing) have been demonstrated to be seen differently by people with and without schizophrenia. These differences in sensory abilities may make it hard for people with schizophrenia to interpret the voices or facial expressions of individuals talking to them. Correction of these basic biological defects — either with medication or with computer training — could have a potentially important therapeutic impact.
Psychosocial and Other Treatment Research
Psychosocial therapies (also called psychosocial rehabilitation and psychiatric rehabilitation) are essential to the treatment of schizophrenia. These include a variety of interventions aimed at restoring a person’s ability to function at home and in the community.
Psychosocial treatments that occur in real-world settings are infinitely more complex and costly to study than more specific interventions that can be studied in a laboratory of other controlled conditions. They often have multiple outcome measures, some of which are more ephemeral to study such as the concept of quality of life (a person’s sense of overall well-being). Sometimes, ethnographic methods (the systematic study of individuals in their own environments) are used to provide qualitative, observational findings to enhance more quantitative ones.
There aren’t the same financial incentives to study psychosocial treatments that there are to study medical treatments. Pharmaceutical industry or other corporate stakeholders are invested in studying medications and devices that will ultimately be patented and profitable. For all these reasons, research on psychosocial treatments has lagged in comparison, and is generally funded exclusively by the federal government, state governments (to a lesser extent), and private philanthropy.
Increasingly the problem of better defining and measuring the “intervention” is being addressed by writing manuals to carefully describe how various psychosocial treatments are to be administered. This has made it possible to carry out credible clinical trials. Also, the goals of some of the newer psychosocial interventions (such as CBT) have become more focused (for example, on reduction of hallucinations or more logical thinking) and briefer rather than global attempts to “make over personality” that were more characteristic of older psychoanalytic approaches, which often took years.
The following psychosocial interventions have been studied extensively and have shown positive outcomes:
Family psychoeducation: Classes and groups involving the person with schizophrenia and her family — or the family alone — to improve mental-health literacy, communication, and coping skills among family members and other caregivers
Supported employment: Employment programs that provide education, training, and a sense of self-worth and productivity
Assertive community treatment: Intensive case management programs that provide outreach and coordinate complex systems of care for individuals wherever they are living
Skills training: Programs designed to help consumers relearn skills of daily living never learned or that they have forgotten because of the illness
Cognitive behavior therapy (CBT): An individual therapy that focuses on changing behavior by changing negative thinking
Cognitive remediation: Aimed at improving cognitive skills impaired by the illness by teaching compensatory strategies to overcome them, similar to that being done with victims of stroke and traumatic brain injuries
Just a few of the other treatment approaches being studied include: individual psychotherapy, family therapy, peer-support groups, self-help groups, consumer operated programs, drop-in centers, clubhouses, assisted and supportive housing programs, and creative therapies (such as art, music, and movement).
Based on the available current research, in order for psychosocial interventions to be effective they must be used along with antipsychotic medications. The two working together provide the most effective treatment, and although there are always exceptions, in general, psychosocial interventions used alone do not result in long-term favorable outcomes.
Evaluating Complementary and Alternative Treatments
Complementary treatments are ones used together with conventional medicine. Alternative treatments are ones used in place of conventional medicine. A variety of complementary and alternative treatments have been tried as treatments for schizophrenia. People seek these treatments because:
They’ve found that other treatments haven’t worked at all or only have addressed some symptoms.
They suffer from uncomfortable side effects of their treatment.
They can’t afford the high cost of prescription medications and conventional psychotherapies.
They strongly desire to use what they see as safer and more “natural” alternatives.
They don’t believe that schizophrenia is a brain disorder and attribute it to other causes (such as nutritional deficiencies).
In the following sections, we cover some of the complementary and alternative treatments that have been studied.
Omega-3 fatty acids
Studies have looked at the use of omega-3 fatty acids as a dietary supplement to reduce the positive symptoms of schizophrenia. These fatty acids aren’t manufactured by the body, so they need to be consumed through foods or dietary supplements. A systematic review of studies by the Cochrane Collaboration (which publishes treatment reviews in all fields of health) found that the effects of essential fatty acid (EFA) supplementation may have some beneficial effects but that the results were inconclusive “due to the limited number of studies and lack of usable data.”
Fish oils (a source of omega-3 fatty acids) cannot be used by people allergic to iodine or who are using blood thinners. Additionally, there is some speculation that EFA-supplements can precipitate mania (excitability).
Antioxidant vitamins
Some research suggests that antioxidant vitamins may be helpful in addressing the negative symptoms of schizophrenia. Foods containing antioxidants include blueberries, prunes, spinach, and strawberries. Although there probably is no inherent danger in eating these foods as part of a balanced diet, again, evidence is inconclusive.
Vitamin E
There is some anecdotal evidence that vitamin E has helped some individuals with tardive dyskinesia (involuntary, repetitive movements of the tongue, lips, face, trunk, and extremities associated with the long-term use of first-generation antipsychotic medications). However, a meta-analysis (a study
of other studies) found that most of the trials that were conducted were too small or of too short duration to provide definitive results. A Cochrane review concluded that the benefits were minimal and might be limited to preventing further deterioration. A large study by the Veterans’ Administration did not show vitamin E to be effective.
In a study conducted to evaluate long-term use of vitamin E to prevent cancer in men and women with vascular disease or diabetes, those taking the vitamin had a 13 percent increased risk of heart failure. An advisory posted on the Web site of the National Center for Complementary and Alternative Medicine (NCCAM) states: “These results emphasize the need to study vitamins and other natural products prior to making public health recommendations.” This cautionary note reinforces that even something as simple as a vitamin may pose serious health risks for certain individuals. Consumers need to be aware of the risks of using yet unproven treatments. At the present time, neither the efficacy nor safety of vitamin E can be recommended as a treatment for schizophrenia.
N-methylglycine
A number of studies have suggested that N-methylglycine (sarcosine), another investigational compound that acts at the NMDA receptor site (see “Glutaminergic approaches,” earlier in this chapter), may improve positive, negative, cognitive, and general psychiatric symptoms in schizophrenia. Because it is investigational, it is still not considered a recommended treatment. Besides, to our knowledge, pharmaceutical-grade sarcosine is not available in the United States.
Acupuncture
Acupuncture has been used as a treatment in China for more than 2,000 years with few adverse effects. A Cochrane review suggests that acupuncture is more socially acceptable, tolerable, and affordable than conventional drugs. However, a review of controlled clinical trials comparing acupuncture to antipsychotics, or using acupuncture as an adjunct to antipsychotics for people with schizophrenia, concluded that there isn’t enough rigorous research to determine its efficacy and that better-designed studies are needed before it can be recommended as a treatment.
The Risks of Unproven Treatments
Eating a nutritionally balanced diet is important for people with schizophrenia — just as it is for everybody else. But many lay people erroneously believe that schizophrenia is caused by poor nutrition. Thus, a range of nutritional therapies — including niacin, vitamin B6, and megavitamins — have been promoted as treatments for schizophrenia, without a credible evidence base supporting their safety or efficacy. For example, flushing and rashes are associated with the use of niacin, and megadoses of vitamins have been implicated in causing health problems.
All food supplements are regulated as foods rather than drugs, so the rules for marketing them are much less restrictive than you may think. Neither safety nor effectiveness has to be proven in order for them to be marketed. In 2003, the FDA published proposed guidelines for supplements that would require accurate labeling and avoidance of contamination with other herbs, pesticides, heavy metals, or prescription drugs.
Bottom line: It’s impossible to draw any positive conclusions about dietary supplements and vitamins as proven treatments for schizophrenia. In general, studies of alternative and complementary treatments for schizophrenia are conflicting, inconclusive, or methodologically weak. Some might even be dangerous.
As with research on conventional medicine, one small study is generally insufficient to prove whether something works. The same holds true for studies of alternative and complementary treatments. What is needed are controlled clinical trials with enough participants and rigorous methods that are repeated with the same results.
In addition to speaking to your medical team, Cochrane Reviews, peer-reviewed meta-analyses, and information from some of the following government agencies can be valuable resources to individuals and families considering use of unconventional treatment approaches:
The National Center for Complementary and Alternative Medicine
(NCCAM), a component of the National Institutes of Health (NIH), is the lead federal agency for research on complementary and alternative medicine. Its Web site (http://nccam.nih.gov) provides a searchable database of the scientific and medical literature on alternative healing practices.
The NIH Office of Dietary Supplements (ODS) seeks to strengthen knowledge and understanding of dietary supplements by evaluating scientific information, supporting research, sharing research results, and educating the public. Its resources include publications and the International Bibliographic Information on Dietary Supplements database(http://ods.od.nih.gov/Health_Information/ IBIDs.aspx).
The Center for Food Safety and Applied Nutrition of the U.S. Food and Drug Administration (FDA) provides information for consumers such as “Tips for the Savvy Supplement User: Making Informed Decisions and Evaluating Information” (www.cfsan.fda.gov/~dms/ds-savvy. html) and updated safety information on supplements (www.cfsan. fda.gov/~dms/ds-warn.html). If you’ve experienced an adverse effect from a supplement, you can report it to the FDA’s MedWatch program, which collects and monitors such information (800-332-1088 or www.fda.gov/medwatch).
Keeping Abreast of Research via the Internet — Wisely
Who can resist the siren call of the Internet when desperately looking for medical information? Open 24 hours a day, anonymous, free of charge, and always accurate — well, maybe not the last. Many people turn to the Internet to learn about medical research, but it’s just as easy to find a quack as it is to find a cure if you believe everything you read. Anyone can start a Web site, and sometimes it seems that every snake-oil salesperson has.
On the other hand, the Internet is a good source of clinical trial reports and the latest research — if you know where to look. Your loved one’s doctor should be keeping abreast of all the research developments in the field that may prove beneficial for her care, but the doctor probably isn’t available 24/7. Just make sure to check out anything that seems exciting or promising with his office on Monday morning!
Social networking sites, user groups, wikis (Web sites that are edited by the public), and other Web sites can all provide useful and interesting information, but embarking on the information highway requires discretion, judgment, and caution.
Here are some things to think about when you’re looking for accurate and unbiased information and trying to evaluate what you read:
Be critical of what you read. Remember that many people post under false identities and that there’s no way to verify what you read without doing more research.
Consider the source of all information. Try to stick with sites sponsored by reputable organizations. The Web address can often help you identify the source of the information. If a Web address ends with .gov, it’s a U.S. government site. If it ends in .edu, it’s likely the site of an educational institution. If it’s .org, it’s a nonprofit. And if it’s a .com, it’s generally a for-profit business. Remember: These are just general guidelines — you may find a .org site that’s not a nonprofit, for example.
Be wary of commercial sites that are selling pharmaceuticals or other products. Make sure the information was derived from clinical trials and isn’t just someone’s opinion. Examine the credentials of the author and his references, usually listed at the end of the article. Find out who provided the funding for the trial and whether there might be any potential conflict of interest. Compare information on the same topic from different sites to see if they provide similar advice.
Chat rooms and forums are rarely a source for solid clinical information.
Rely only on current information. Every major page of a Web site should include the date that it was written or reviewed. Whenever possible, rely only on material that includes a date. On some sites, no one verifies whether information is still accurate or whether it became obsolete long ago.
Read only user-friendly material. There are many, many sites to choose from, so be sure to use those that are easy to read and navigate. Don’t waste your time trying to find information embedded in poorly designed Web sites.
Be cautious about sharing private information. On the Internet, you can’t be sure that information you divulge will remain private, so you need to be cautious. Before you fill out any forms or reveal any information about yourself or your family, make sure you review the site’s privacy policy. When you post messages in chat rooms or on bulletin boards, consider using a pseudonym instead of your real name.
Remember that the Internet cannot substitute for medical advice. Given all these caveats, always be judicious in your use of the Internet as a source of definitive information concerning mental-health issues.
By exercising appropriate caution, the knowledge you get from the Web can help you become more literate about mental health, help you learn what questions to ask, and enable you to better communicate with professionals.
