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How to Research Your Symptoms Online
People use the Internet to research a myriad of things from what they should buy to why they have pain. These guidelines will help you learn how to research your symptoms online if you have concerns.
Use a Medical MD Symptom Checker
As soon as you enter the phrase, “how to research health symptoms,” into any search engine, you’ll receive results for at least one or more reputable medical MD symptom checkers. These symptoms checkers ask your age, gender, primary symptoms, if you’re pregnant, the severity of your symptoms, your current medications and past or current conditions. Once you click submit, a list of conditions that match your symptoms will appear. You’ll have the option to edit your symptoms or start over if you wish.
Check Reputable Websites
If you can’t find what you’re looking for using a free medical symptom checker, there are websites with articles or blog posts that list symptoms. Make sure you’re looking at reputable websites that end with .org or .edu because these sites tend to contain scholarly or medical information that can be trusted. The Internet is full of information that’s published and not verified. Therefore, it’s essential that you’re looking up symptoms on a website that presents information that’s been fact-checked.
Go to a Doctor’s Website
Under some circumstances, you’ll find an online symptom checker on a physician’s website. If you can’t find a MD symptom checker, you’ll find a plethora of resources on these websites. Doctors work diligently toward providing information for their patients in the way of medical library research materials, informational articles, blog posts and podcasts. Therefore, if you can find a symptom checker, you should be able to find information about the symptoms you’re experiencing.
Visit Forums
Sometimes it helps to hear what others are experiencing when you’re undergoing symptoms that don’t match up with the search results you’ve found. Therefore, it’s time to check out user forums. These discussion areas contain experiences from users who go into detail about the symptoms they’re having, what’s happening throughout their experience and if they’re having successful or unsuccessful treatment. Be cautious, though, as these forums will not replace medical advice and may lead to more worry than help.
Check Out Question-and-Answer Websites
Much like a discussion forum, these websites are where users post specific questions to other users regarding issues they’re experiencing. Under many circumstances, these questions pertain to symptoms they’re experiencing and where they can find resources. Other users will help them find pertinent information regarding their specific symptoms when they feel they’ve exhausted every other avenue.
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Researchers Discover Second Type of Schizophrenia
In a study of more than 300 patients from three continents, over one third had brains that looked similar to healthy people., february 27, 2020.
PHILADELPHIA – Penn Medicine researchers are the first to discover two distinct neuroanatomical subtypes of schizophrenia after analyzing the brain scans of over 300 patients. The first type showed lower widespread volumes of gray matter when compare to healthy controls, while the second type had volumes largely similar to normal brains. The findings, published Thursday in the journal Brain , suggest that, in the future, accounting for these differences could inform more personalized treatment options.
“Numerous other studies have shown that people with schizophrenia have significantly smaller volumes of brain tissue than healthy controls. However, for at least a third of patients we looked at, this was not the case at all — their brains were almost completely normal,” said principal investigator Christos Davatzikos, PhD, the Wallace T. Miller Professor of Radiology in the Perelman School of Medicine at the University of Pennsylvania. “In the future, we’re not going to be saying, ‘This patient has schizophrenia,’ We’re going to be saying, ‘This patient has this subtype’ or ‘this abnormal pattern,’ rather than having a wide umbrella under which everyone is categorized.”
Schizophrenia is a poorly understood mental disorder that typically presents with hallucinations, delusions, and other cognitive issues — though symptoms and responses to treatment vary widely from patient to patient. Up until now, attempts to study the disease, by comparing healthy to diseased brains, has neglected to account for this heterogeneity, which Davatzikos says has muddled research findings and undermined clinical care.
To better characterize the distinct brain differences within the schizophrenia patient population, Davatzikos established a research consortium that spanned three continents — the United States, China, and Germany. The international cohort of study participants included 307 schizophrenia patients and 364 healthy controls, all of whom were 45-years-old or younger.
Davatzikos and engineering colleagues then analyzed the brain scans using a machine learning method developed at Penn called HYDRA (Heterogeneity Through Discriminative Analysis). The approach helps to identify “true disease subtypes” by limiting the influence of confounding variables, such as age, sex, imaging protocols, and other factors, according to the study authors.
“This method enabled us to sub-categorize patients and find how they differed from the controls, while allowing us, at the same time, to dissect this heterogeneity and tease out multiple pathologies, rather than trying to find a dominant pattern,” Davatzikos said.
After applying this machine learning method to the brain images, the researchers found that 115 patients with schizophrenia, or nearly 40 percent, did not have the typical pattern of reduced gray matter volume that has been historically linked to the disorder. In fact, their brains showed increases of brain volume in the middle of the brain, in an area called the striatum, which plays a role in voluntary movement. When controlling for differences in medication, age, and other demographics, the researchers could not find any clear explanation for the variation.
“The subtype 2 patients are very interesting, because they have similar demographic and clinical measures with subtype 1, and the only differences were their brain structures,” said Ganesh Chand, PhD, a lead author and postdoctoral researcher in the radiology department at Penn.
There are a variety of antipsychotic medications available to manage the symptoms of schizophrenia, but how they will affect a particular patient — both positively or negatively — is often a shot in the dark, according to study co-senior author Daniel Wolf, MD, PhD, an associate professor of Psychiatry at Penn.
“The treatments for schizophrenia work really well in a minority of people, pretty well in most people, and hardly at all in a minority of people. We mostly can’t predict that outcome, so it becomes a matter of trial and error,” Wolf said. “Now that we are starting to understand the biology behind this disorder, then we will hopefully one day have more informed, personalized approaches to treatment.”
As to why an entire subset of patients with schizophrenia have brains that resemble healthy people, Davatzikos is not willing to speculate.
“This is where we are puzzled right now,” Davatzikos said. “We don’t know. What we do know is that
studies that are putting all schizophrenia patients in one group, when seeking associations with response to treatment or clinical measures, might not be using the best approach.”
Future research, he said, will provide a more detailed picture of these subtypes in relation to other aspects of brain structure and function, clinical symptoms, disease progression, and etiology.
This research was funded by the National Institutes of Health grant R01MH112070 and by the PRONIA project as funded by the European Union 7th Framework Program grant 602152.
The study included 28 co-authors from the United States, Germany, China, the United Kingdom, the Netherlands, Brazil, Spain, Italy, and Australia, who were affiliated with 15 universities worldwide.
Additional Penn authors include: Guray Erus, Aristedidis Sotiras, Erdem Varol, Dhivya Srinivasan, Jimit Doshi, Raymond Pomponio, Taki Shinohara, Ruben C. Gur, Raquel E. Gur, Russell T. Shinohara, Haochang Shou, Yong Fan, and Theodore D. Satterthwaite.
Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System , which together form a $9.9 billion enterprise.
The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $546 million awarded in the 2021 fiscal year.
The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.
Penn Medicine is powered by a talented and dedicated workforce of more than 47,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2021, Penn Medicine provided more than $619 million to benefit our community.
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- v.1(4); 2008 May
Schizophrenia: Current Concepts and Approaches to Patient Care
Peter f. buckley.
Professor and Chair, Department of Psychiatry and Health Behavior, Medical College of Georgia, Atlanta
Adriana Foster
Assistant Professor, Department of Psychiatry and Health Behavior, Medical College of Georgia, Atlanta
Schizophrenia is the most serious of all mental conditions. It is typically a long-lasting condition characterized by repeated relapses and by marked functional impairment. Genetic and environmental factors are important. Exactly which factors and how these combine to cause schizophrenia is still unclear. Antipsychotic medications form the bedrock for treatment. These drugs are effective, but not entirely so, and are associated with negative side effects. Individual differences among the available medications suggest that trials with a different medication may be appropriate when one agent fails or is not appropriate for the specific patient. Monitoring for side effects is important to ensure efficacy and compliance. Often, patients choose to stop taking their medications for a variety of reasons, which invariably will lead most patients to a relapse of illness. Beyond medications, patients need considerable support and specialized services. Families are a key resource. The recent focus on personal determination has led to recovery-based services, including the incorporation of peer support into patient care.
Schizophrenia is a poorly understood condition. Despite several recent documentaries and movies depicting the course and disability of this illness, the lay public remains largely confused about schizophrenia and continues to harbor notions that it is a “split personality” or a “Jekyll and Hyde” phenomenon. Regrettably, efforts to articulate a clear account of what schizophrenia really is and what causes it have been hampered by a lack of compelling evidence as to its etiology. Despite the many clues to the cause(s) of schizophrenia, definitive evidence is still lacking. In many ways, we can be more dogmatic about what is not relevant to schizophrenia ( Table 1 ). This is important because stigma, which is fueled by a lack of knowledge, is a major obstacle in managing schizophrenia. Several books provide comprehensive information about schizophrenia. 1 – 4 This article offers a current overview of schizophrenia and its treatment.
Dispelling Common Myths about Schizophrenia
Schizophrenia is a complicated diagnosis. The condition is characterized by delusions (fixed, false beliefs), hallucinations (typically “hearing voices” when no one is around), disturbances of speech (illogicality, nonlinearity of thought and conversation), restricted affect and emotionality, and impairments of thinking (memory, attention, reasoning, awareness).
- ▴ Schizophrenia is the most serious of all mental conditions and is characterized by repeated relapses and significant functional impairment.
- ▴ Diagnosis requires a psychotic episode that lasts at least 6 months.
- ▴ Continuous use of antipsychotic medications is the mainstay of therapy.
- ▴ Patient lack of compliance will inevitably lead to relapse and may have serious consequences.
- ▴ The new-generation antipsychotics are slightly more effective but their metabolic side-effect profile is a serious concern, requiring ongoing monitoring by the treating physician.
Given the impact of such a constellation of symptoms, the condition is typically associated with a decline in social and/or occupational performance. Indeed, this may be what parents, friends, or coworkers notice first—a withdrawal, dropping out of college, or inability to cope with the stress of work. For many patients, the onset of such “disintegration” is insidious. Others have a florid presentation, manifest by prominent delusions, hallucinations, and bizarre behaviors, such as locking oneself in an elevator at a mall and shouting out, “Aliens, go away.”
Although such a presentation may lead some to wonder “how hard can it be to diagnose this person as psychotic,” the presentation could (and in fact is likely to) be complicated by abuse of drugs. This complicates things considerably. Also, many people who develop schizophrenia become depressed as the illness evolves. It can be difficult to determine whether the person is suffering from major depression or is in the early stages of a psychotic illness. It is therefore best to wait and see how things play out definitively over months before making such a serious diagnosis as schizophrenia ( Table 2 ).
Diagnostic Features of Schizophrenia
Schizophrenia typically begins in adolescence or in early adulthood. It occurs equally in males and females, but the onset is on average 4 years later in females, and the illness tends to be milder in females. The reasons for these gender differences are not yet known.
Practically, the Diagnostic and Statistical Manual of Mental Disorders mandates that clinicians classify this illness as “schizophreniform disorder” if the duration is less than 6 months. 5 This is because some patients have a single psychotic episode, which looks indistinguishable from schizophrenia, but they will regain normal functioning without any recurrence. Similarly, those who abuse drugs such as cannabis can have a psychotic break that appears like schizophrenia, but they, too, will regain normal functioning without further episodes once they quit taking the drugs. This latter condition is classified as a “drug-induced psychosis.” 6
Causes(s) of Schizophrenia
Ultimately, we do not know what causes schizophrenia, 1 , 7 , 8 but we do know that it runs in families and is associated with birth complications, head injury, epilepsy, and drug abuse. Cannabis abuse raises one's risk for schizophrenia by about 4.5-fold. Recent research suggests that people who have a genetic vulnerability are 16 times more likely to become psychotic when they abuse cannabis.
An ongoing debate about the causes of schizophrenia is whether any particular insult (eg, genetic defects, birth complications) leads to this condition (like the model of multiple causes of elevated blood pressure) or, alternatively, whether each of these insults can cause a psychotic condition that has a different cause but is similar in presentation and fits under the rubric of schizophrenia (as in pneumonia, whether caused by influenza virus or by bacteria).
Genetic component
Whether schizophrenia is a single illness or multiple illnesses has not yet been teased out, but we do know it has a strong genetic basis, which puts blood relatives at risk ( Table 3 ). Genetic studies have shown abnormalities on several chromosomes (eg, chromosome 5, 8, 11, 13, 22). 9 However, as with many aspects of schizophrenia, the findings are inconclusive and do not point to a precise gene involved. More recent genetic studies have focused on the search for abnormalities in genes or their related proteins that are involved in neuronal development (eg, dysbindin, neuregulin, SNAP-25 , brain-derived neurotrophic factor). 10
Risk of Developing Schizophrenia If Blood Relative Is Ill
Source: Gottesman II, Shields J. Schizophrenia: The Epigenetic Puzzle . Cambridge University Press, Cambridge, UK; 1982.
Birth factors
One of the most reproducible findings in schizophrenia is that affected patients are far more likely to have been born in the first 3 months of the year—the so-called season of birth effect. 11 This curious, yet robust, association points to birth or to the time in utero as relevant to the development of schizophrenia.
Another reproducible finding is that about 20% of people who develop schizophrenia have had some sort of birth complication, 12 such as a prenatal exposure to influenza, haemolytic anemia, severe malnutrition, preeclampsia, asphyxia, or fetal distress. This could, of course, have something to do with the pregnancy and with the delivery itself. For example, the fetus may experience hypoxia in the birth canal, which could result in minimal brain damage that manifests later in adolescence as schizophrenia. Alternatively, the birth complication may occur because the fetus itself is “defective.” Brain development in utero might have gone wrong in some way because of genetic misprogramming or because of some external injury (eg, a mother with an infection during the critical first 3 months of pregnancy).
Brain abnormalities
There is evidence that brain development is disturbed in schizophrenia. The evidence comes from postmortem brain studies of people with schizophrenia who died from natural causes (eg, a heart attack, although this could also influence or bias postmortem brain findings) or from suicide (clearly, this could affect the brain). 10 , 13 Although this type of research has its own methodological problems, these studies have shown convincing evidence of abnormal (underdeveloped) cells and of cells that are misplaced or misaligned in the brains of people with schizophrenia. 10 , 13
These subtle findings occur more often in the temporal lobes than in any other brain regions. Modern brain imaging techniques (eg, magnetic resonance imaging [MRI]) facilitate the study of live brains of people with schizophrenia, revealing fairly reproducible findings ( Table 4 ). 14 , 15 Some studies have also included relatives of patients with schizophrenia as a comparison group. 16 , 17 These reveal much milder, but the same, findings in healthy relatives (who “do not have the illness” but may have genes susceptible to schizophrenia). This raises the question whether such brain abnormalities are present from birth or even before the onset of schizophrenia.
Abnormal Brain Structure Findings in Imaging Studies of Patients with Schizophrenia
Sources: References 13, 14.
There have been efforts to tease this out. Studies of patients in their first episode of psychosis show the same patterns of abnormalities on brain imaging, 18 but in a more attenuated form, as seen in first-episode patients with chronic schizophrenia. Other studies involve “prodromal” populations, namely, patients who have not had a psychotic episode yet but who show “mild” signs of schizophrenia (eg, oddities of thought and speech). These patients show even “milder,” barely detectable, brain abnormalities. In one such study, the prodromal patients who went on to have a psychotic break had more temporal lobe abnormalities on MRI than patients who did not progress to psychosis. 19
Collectively, these findings, which point to faulty early brain development, have led many to consider that schizophrenia may be a neurodevelopmental disorder ( Table 5 ). 1 , 7 , 20 That is, people with schizophrenia may have an aberrant development of brain “hardwire” (eg, misplaced, misaligned, or immature cells; faulty neural communication tracks). It is postulated that as time goes by, these cortical vulnerabilities become exposed as the patient progresses toward psychosis. Some have suggested that the reason for the onset of psychosis at adolescence is a clue. This is a time of brain “rewiring” and plasticity. With these changes, the otherwise “dormant” brain abnormalities are now exposed. Others have postulated that given this brain vulnerability from birth, other events (eg, drug abuse, stress) during adolescence may also push the person (ie, brain) “over the edge” to cause psychosis. This “2-hit” notion is also an intuitively appealing hypothesis. All these reflect the notion that schizophrenia is a neurodevelopmental disorder, and as with other such disorders (eg, cerebral palsy), the causes may be genetic, environmental, or both.
Evidence for Schizophrenia as a Neurodevelopmental Disorder
Kraepelin, the German psychiatrist who first described schizophrenia in 1896, considers this to be a dementing condition. He describes how schizophrenia evolves in adolescence and progresses inexorably into a chronic state (which he called “dementia praecox,” dementia of youth).
Seemingly in direct opposition to the brain-imaging evidence that supports the neurodevelopmental hypothesis in schizophrenia, other, long-term imaging studies report a progressive loss of brain tissue. 21 , 22 This would favor a neurodegenerative hypothesis of schizophrenia (like Huntington's disease). Some have suggested that schizophrenia may have both neurodevelopmental and neurodegenerative processes at work. Under such a parsimonious scheme, it is proposed that the underlying neurodevelopmental brain vulnerability predisposes to a more progressive brain loss. 23 A precedent for this viewpoint is Down syndrome (DS), which is a prototypical neurodevelopmental disorder caused by chromosomal abnormalities. Patients with DS show a variety of neurodevelopmental features clinically (see Table 5 ), and they also have mental retardation. Patients with DS develop Alzheimer's-like dementia very early on, typically in their 40s. Therefore, some have suggested that a 2-process model may also explain schizophrenia. But as elegant as each of these hypotheses are, they are also very difficult to prove or refute.
The weight of evidence currently favors a neurodevelopmental basis for schizophrenia. It is plausible that some patients could have a neurodevelopmental form of schizophrenia, while others may have a neurodegenerative schizophrenia. 20 The complexity of the process involved and the lack of a clear understanding lessen our ability to give a clear picture about schizophrenia to the public.
Brain Chemistry and Schizophrenia
Overactivity of the dopamine neurotransmitter system is the most compelling neurochemical abnormality in schizophrenia. 24 This is also the most easily explained theory for the public—people become psychotic because their dopamine is overactive. There is certainly evidence for this, including functional brain-imaging studies that show excess of dopamine in the brain of patients when they are acutely psychotic. But like all the other explanations of schizophrenia, it is not quite as simple as “too much dopamine.” Some researchers have suggested there is overactivity of dopamine in one brain region (eg, temporal lobes), concomitant with underactivity in another area (eg, frontal lobes). Also, the fault may not be across all dopamine receptors but perhaps selectively in some of the subclasses of dopamine receptors or beyond the actual receptors, even as a subsequent maleffect in cell-signaling.
It is clear that other neurotransmitter systems are affected in schizophrenia. The neurotransmitter systems implicated in this disease are:
- Cholinergic
- Glutamatergic
- Noradrenergic
Deficits in other neurotransmitter systems (eg, glutamate receptors) may underlie schizophrenia directly and/or indirectly through their interrelated effects on the dopamine system. 25 Thus far, the dopamine system has been the most pronounced neurochemical abnormality and, significantly, appears to be related to how patients respond to treatment.
Treatment of Schizophrenia
It is hardly surprising, given the complexity of the condition, that effective treatment of schizophrenia requires attention to multiple components of care. It is true that medications form the bedrock of treatment, but medications alone are not enough to keep people stable and/or to achieve recovery. 1 , 3 , 26 , 27 Elements of comprehensive care for patients with schizophrenia are listed in Table 6 .
Elements of Comprehensive Care for Patients with Schizophrenia
Antipsychotic medications
Antipsychotic medications are the mainstay of treatment ( Table 7 ). Although all currently available antipsychotics act on the dopamine system (invariably to block dopamine D 2 receptors and are therefore considered to work by “turning off” the overactive dopamine receptors), this is likely to be too simplistic. Antipsychotic medications also have a variety of agonist (activating) and antagonist (deactivating) effects on several other neurotransmitters. Pharmaceutical companies have targeted the development of highly selective drugs (eg, a dopamine D 4 antagonist) or more “gunshot” drugs that have effects at multiple receptors (“pleomorphic” antipsychotics, such as clozapine [Clozaril] or olanzapine [Zyprexa]). The exact “magic potion” for treating schizophrenia remains a mystery. For now, the available medications are effective, but with limitations ( Table 8 ).
Selected First- and Second-Generation Antipsychotic Medications: General Information *
IM indicates intramuscular.
$ 0–25
$$ 26–50
$$$ 51–100
$$$$ 101–200
$$$$$ >200
Source for cost: Lexi-Comp, at www.drugstore.com .
Safety and Tolerability of First- and Second-Generation Antipsychotics
Note: This table gives an overall impression of the side-effect profile. For individual drugs, clinicians should consult the approved product labeling and/or the most current Physicians' Desk Reference manual.
A thorough account of the psychopharmacology of schizophrenia is beyond the scope of this article. Some general comments on the treatment of schizophrenia are more appropriate.
1 . With the exception of clozapine, the other antipsychotics are more similar than different in their ability to control the symptoms of schizophrenia. 28 , 29 All of them are effective in relieving acute symptoms—anxiety, agitation, delusions, and hallucinations. Some may act a bit quicker (or perhaps are easier to get quicker to an effective dose) and some may be more powerful in their effect on symptoms (again, dosing may play a big role here).
The older (also known as conventional, typical, or first-generation) antipsychotic medications have proved efficacy and work best against positive symptoms, with little benefit for negative, depressive, or cognitive symptoms (they may even worsen these aspects of the illness). Their major adverse side effects are related to their antagonism of the dopamine system. These drugs cause acute and chronic muscle (extrapyramidal) side effects that are distressing and disfiguring. Because they have been around for a long time, they are relatively inexpensive.
The new antipsychotics, also known as atypical or second-generation antipsychotics, show similar or slightly better efficacy compared with the first-generation agents in treating positive symptoms. They have variable, but generally only modest, benefits in treating negative, depressive, and cognitive symptoms. Although these medications generally have a lower risk for extrapyramidal side effects than the first-generation agents, they have other serious side effects, as reflected in Table 8 .
More so than the first-generation antipsychotics, the newer agents cause weight gain and metabolic disturbances of glucose, insulin, cholesterol, and lipids. 29 , 30 This is a major drawback, which has substantially complicated the treatment of schizophrenia and is currently the number-one issue in the psychopharmacology of schizophrenia. Treating physicians are monitoring patients carefully to detect such disturbances and are also concerned about switching medications and seeking relief in another antipsychotic when these problems emerge.
These drugs are also remarkably expensive, which limits access and imposes high financial burden on an already overburdened mental healthcare system. In contrast, if these (or any particular) drugs keep a patient from relapsing and avoiding hospitalization, then the medication is cost-effective.
2 . Although antipsychotics are generally effective (better in acute care and for positive symptoms), a substantial group of patients remains unwell. Some patients relapse frequently over time; some are chronically psychotic, and the medications barely work for them. Efforts to help these patients include:
- Trials of high doses of an antipsychotic
- A trial of 2 antipsychotics together
- Trials of add-on drugs (eg, antidepressants, stimulants) that may boost the effect of the antipsychotics
- Use of clozapine (the most powerful of all antipsychotics but with a high side-effect burden)
- For intractable situations, as well as for severe depression or catatonia, a trial of electroconvulsive therapy. There is also a particular interest at present in finding ways to reduce the cognitive deficits of schizophrenia, which are rate-limiting obstacles to recovery. 31
3 . The side-effects burden of the antipsychotics is substantial. Clinicians engage in a trial-and-error process with patients in an effort to find the drug that will work best and will result in fewer side effects. The sensitivity of each patient is unique—both in terms of the ability to respond to one drug (but perhaps not to another) as well as to experience the side effects.
The response and tolerability of each patient is individualized. We can make general predictions about the overall risk-benefit profile of any given drug, but how a patient will fare in practice is the true test. In addition, the dose of the medication strongly influences both response and tolerability. At present, the selection, dosing, and use of antipsychotics in clinical practice are more art than science. Efforts toward personalized medicine and toward the emergent strategy of pharmacogenetics (the genetics of medication response and side-effect prediction) offer future hope.
4 . Regardless of the benefits and drawbacks of the medications themselves, our ability to treat schizophrenia is curtailed even more by the patient's reluctance to take antipsychotic drugs and to continue using medications. 32 Estimates differ by each study, but approximately 50% of patients are noncompliant with their prescribed antipsychotic medication regimen. 33 Most are partially noncompliant, missing medications “here and there.” Some patients are noncompliant and “learn the hard way,” by having recurrent relapses of illness. Some patients remain noncompliant with treatment and, as a result, are extremely difficult to treat.
When at imminent risk to themselves or others, patients can be hospitalized against their will and be forcibly medicated until their illness is stabilized. The problem then recurs, however, when they are discharged from the hospital. To combat medication noncompliance, patients can receive their antipsychotic medication in an injectable form that provides continuous treatment over weeks, usually 2 to 4 weeks. Some clinicians believe that this strategy is underutilized and should become more mainstream rather than be confined to patients who refuse their medications.
Comorbidities complicate treatment
In addition to the complexity of the illness itself, patients with schizophrenia are likely to have other psychiatric and/or medical comorbidities over the course of their illness, as outlined in Table 9 .
Psychiatric and Medical Conditions Associated with Schizophrenia
Social aspects of treating mental illness
Beyond medications, patients need a huge amount of support. 34 The greatest support patients can get—and do get—is from their families. Relatives provide love, emotional support, housing, and financial assistance. They are also the people who know the patient best and can be watchful for signs of relapse. However, the emotional strain of caring and living with someone who is suffering from schizophrenia can be overwhelming. Relatives also need support. They need education on the latest treatments, as well as tips on how to manage difficult situations. Organizations such as the National Alliance for Mental Illness are an invaluable resource.
Patients also need psychological support from mental health professionals. Patients benefit from counseling and supportive psychotherapy. There are also programs that focus on social skills training, helping patients to make friends and to reintegrate into the community. Most patients do not work; if they do, it is often at a low-paying job. Although it is clear that active psychosis and cognitive deficits reduce the capacity of people to hold down jobs (especially stressful jobs), it is also evident that having a job is a powerful motivator for healthy living and boosts self-esteem.
There are now efforts to train people and to enhance their cognitive abilities so that they will be able to sustain in employment. 35 Our system is poorly constructed to help people get, and hold jobs. Sometimes patients are faced with the painful decision of taking a job and losing their Medicaid support, because they now earn a wage. These situations expose some of the many ways that our society discriminates against people with mental illness.
Similar to the role of sponsors in Alcoholics Anonymous, patients with serious mental illness are now also helping other patients to recover. 36 These “peer-support specialists” can be powerful catalysts for change, for individual patients and for systems of care through their roles as advocates. This is a powerful approach that broadens the focus of care toward more meaningful, life-attainment goals. It also instills personal responsibility and hope in patients.
Hope is a powerful catalyst in coping with illness. The notion that some people can recover from serious illnesses like schizophrenia is powerful. 37 Important components of recovery for people with serious mental illness include hope, spirituality, and empowerment. 37
Patients with more severe illness require continuous support to help them live in the community. This service is delivered by a community psychiatric team comprised of case managers, with each team serving just a few patients. This labor-intensive approach, called “assertive community treatment” (ACT), works well to maintain patients in the community. Although its staffing costs are high, it is still cost-effective, because ACT dramatically reduces days spent in a hospital.
Schizophrenia is a challenging condition to diagnose and to treat. The lack of insight that is so common with the condition could undermine (through treatment nonadherence) the efforts of family and mental health professionals to provide comprehensive care. The potential for comorbidities further adds to the complexity of the illness and will require additional psychiatric and/or medical treatment. These further complicate already arduous clinical circumstances. Patients with schizophrenia need comprehensive care, compassion, and support. They deserve this.
AHDB Stakeholder Perspective
The approach to schizophrenia.
PAYORS: Payors have had a difficult time understanding how to approach schizophrenia. In the private sector, payors are accustomed to taking action when possible. Employers expect contracted insurance companies to take action on their behalf whenever it makes sense. This disease state, however, does not lend itself to such a direct treatment approach. Patients with schizophrenia-related disorders are often reluctant to adhere to medication regimens. The results are often viewed in one of two ways: The sick member who avoids medication, or the sick member who takes expensive medications in a nonadherent manner—both of which result in less-than-optimal health.
The major payors in this arena are state Medicaid agencies. Medicaid dollars pay for a substantial amount, perhaps half, of all prescriptions for schizophrenia, and must then pay for all related healthcare costs. So what are the goals of these state agencies? The states seek to ensure that people have access to care. Unfortunately, effectiveness is secondary to access.
This theme seems to be consistent regardless of who the payor is—private or public. As we do for other disease states, the payor community should push for a metric that demonstrates effective care for the patient with schizophrenia. Granting access to a random assortment of nonadherent monotherapies and combination therapies is not the answer. We should strive to ensure that patients and their providers make valiant attempts at treatment protocols before abandoning them in favor of the next horse on the schizophrenia drug carousel.
In the 1970s, advocates fought against the use of “depo-products” (eg, injected haloperidol) on the basis that some patients were overmedicated, and that one did not have the ability to immediately reverse the course of treatment if desired when using such extended-release products. Over the past 35 years, reverting to daily oral medications as standard treatment has witnessed the reemergence of patient nonadherence. A call for a return to forced medication has now been heard to redress the situation. Where shall it go from here?
PATIENTS: Ultimately, the direction should be determined by what is best for the patient. Neither legal advocates interested in outlawing extended-release medications as a civil rights infringement, nor state agencies willing to throw the entire medicine cabinet at patients without regard to medication effectiveness, should be making this decision.
Michael Schaffer, PharmD
Director of Pharmacy, HealthMarkets, Philadelphia, PA
Prior Authorization for Antipsychotics Complicates Adherence
BENEFIT MANAGERS: The question of open versus restrictive access to the newer (atypical) antipsychotic medications lingers, as prior authorization (PA) and step-edit policies are being used to control costs, 1 and nonadherence remains a major concern. In his article, Dr Buckley notes that schizophrenia is the most serious mental condition, which requires optimal therapy.
Findings from a study just published in Health Affairs and led by Dr Steven B. Soumerai of Harvard Medical School's Department of Ambulatory Care and Prevention “provide strong evidence of both intended and unintended consequences of the Maine PA policy” 2 implemented in a Medicaid program from July 2003 through March 2004. Dr Soumerai and colleagues compared antipsychotics use in the Maine program pre- and postimplementation of the PA policy; an open access Medicaid program in New Hampshire was used as control. The Maine PA policy resulted in a 29% greater risk of treatment discontinuation compared with the period before implementing the PA policy. 2 No differences in discontinuation risk were found in the New Hampshire program.
The authors concluded that “the most adverse clinical outcome was treatment discontinuation, which is a strong predictor of acute psychotic episode, hospitalization, and other negative clinical and economic outcomes. Pharmacy savings were minimal.” 2 They admit that restrictive policies may control costs when applied to more homogeneous drug classes (eg, nonsteroidal anti-inflammatory drugs or angiotensinconverting enzyme inhibitors), but because of marked differences in patients' response to antipsychotics, such tools are not productive and can be harmful when used for antipsychotics the authors say. In an interview with Newswire, Dr Soumerai said, “Given the tremendous variation in individual responses to these drugs as well as the devastating impact of treatment disruption on schizophrenic patients, a policy that pushes all patients toward a limited number of preferred drugs may do more harm than good.” 3
More than 30% of Medicare Part D and Medicaid programs have PA policies for antipsychotics. 1 , 2
Peter F. Buckley, MD
Disclosure Statement
Dr Buckley receives grant/research support from AstraZeneca, National Institute of Mental Health, Pfizer, Solvay, and Wyeth; is a consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceutica, Lundbeck, Pfizer, Solvay, and Wyeth; and receives honoraria from Bristol-Myers Squibb, Janssen Pharmaceutica, Lundbeck, and Pfizer.
Contributor Information
Peter F. Buckley, Professor and Chair, Department of Psychiatry and Health Behavior, Medical College of Georgia, Atlanta.
Adriana Foster, Assistant Professor, Department of Psychiatry and Health Behavior, Medical College of Georgia, Atlanta.
- Schizophrenia
Latest Schizophrenia Research
Science is key to learning more about health conditions, including mental illness . While experts still don’t fully understand all aspects of schizophrenia , the number of research studies published over the past 25 years, has quadrupled. Research continues to offer insight into the illness’s causes, diagnosis, and treatment.
Schizophrenia Causes
Researchers aren’t exactly sure what causes schizophrenia, but they’ve identified several possible reasons which may combine to put people at risk. And they’re using cutting-edge technology to make discoveries.
One area of research that’s shown progress is the role of genes. Scientists recently published the largest-ever whole-genome sequencing (WGS) study of schizophrenia. WGS is a technology that shows the entire DNA make-up. It also helps researchers to better understand differences within and between living things.
Using WGS, researchers in the schizophrenia study noticed DNA changes (mutations) that scientists had never seen before. They suggest that certain differences in the boundaries of your DNA structure raise your risk of the disease. Researchers found these changes more often in people with schizophrenia. How those changes are involved in the condition remains to be seen.
Brain connections
Advances in technology have also allowed researchers to find new clues into schizophrenia inside the brain . For the first time, brain scans of people with schizophrenia show lower levels of a protein found in the connections between neurons (special cells in the nervous system that send information to other cells).
Researchers used positron emission tomography (PET) scans to track a radioactive substance injected into the brain called a tracer, which binds to the SV2A protein. In people with schizophrenia, this protein was lower in the part of the brain involved in planning. The significance of this in schizophrenia isn’t clear yet.
Until now, researchers were only able to study these brain connections in animals or people who had died. Researchers say the discovery could lead to new treatments for memory-related symptoms. Right now, schizophrenia treatments only target symptoms of psychosis like delusions.
Schizophrenia Diagnosis
In recent years, the American Psychiatric Association (APA) and the World Health Organization (WHO) have revised their suggestions for how health care providers should classify and diagnose schizophrenia. They recommend:
- No longer grouping the illness into subtypes like paranoid schizophrenia
- Putting less weight on certain symptoms and more on others like delusions and hallucinations
- Focusing more on how long someone has had symptoms (1-6 months) and figuring out if other things could be causing them
- A rating system to gauge both the mental and physical symptoms of schizophrenia
Schizophrenia Treatments
As researchers learn more about schizophrenia, how they treat the disease continues to evolve.
New medications
Most schizophrenia medicines target the chemical brain messenger (neurotransmitter) dopamine . But researchers are working on a new generation of drugs aimed at other neurotransmitters. They could ease:
- Cognitive symptoms, or problems with memory, thinking, and judgment
- Side effects of current drugs like uncontrolled movement and heart rhythm problems
- “Negative” symptoms of schizophrenia like reduced pleasure, social activity, and expression of emotion
Targeted psychotherapy
Many studies over the past 20 years show that psychotherapy works well to ease schizophrenia symptoms. Beyond treating overall mental health , today, psychotherapy research focuses on specific schizophrenia symptoms like hearing things that aren’t really there ( auditory hallucinations ). Results are promising, and researchers say this targeted treatment could be another option to traditional therapy .
Brain stimulation
Other possible new schizophrenia treatments involve the brain:
- Transcranial magnetic stimulation (TMS) uses magnetic fields to stimulate nerve cells in your brain. It’s painless, doesn’t require cutting.
- Deep brain stimulation ( DBS ) uses electrical pulses to balance abnormal impulses or certain cells and chemicals. DBS does require surgery to place electrodes and the device that controls them inside your brain.
These treatments could be an alternative to medication, but scientists will need to do more research to find out if they work for people with schizophrenia.
Schizophrenia Research Outlook
While new treatments could help people with schizophrenia in the future, researchers say the best approach is to advance treatments available right now.
Studies show about half of all people with schizophrenia don’t get treatment for the illness. More information about symptoms, available treatments, and access to mental health services could bridge the gap. Researchers also say that mental health programs should address stigma and prejudice against people with mental illness .
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Schizophrenia
- Schizophrenia causes psychosis and is associated with considerable disability and may affect all areas of life including personal, family, social, educational, and occupational functioning.
- Stigma, discrimination, and violation of human rights of people with schizophrenia are common.
- More than two out of three people with psychosis in the world do not receive specialist mental health care.
- A range of effective care options for people with schizophrenia exist and at least one in three people with schizophrenia will be able to fully recover.
Schizophrenia is characterised by significant impairments in the way reality is perceived and changes in behaviour related to:
- persistent delusions: the person has fixed beliefs that something is true, despite evidence to the contrary;
- persistent hallucinations: the person may hear, smell, see, touch, or feel things that are not there;
- experiences of influence, control or passivity: the experience that one’s feelings, impulses, actions, or thoughts are not generated by oneself, are being placed in one’s mind or withdrawn from one’s mind by others, or that one’s thoughts are being broadcast to others;
- disorganized thinking, which is often observed as jumbled or irrelevant speech;
- highly disorganised behaviour e.g. the person does things that appear bizarre or purposeless, or the person has unpredictable or inappropriate emotional responses that interfere with their ability to organise their behaviour;
- “negative symptoms” such as very limited speech, restricted experience and expression of emotions, inability to experience interest or pleasure, and social withdrawal; and/or
- extreme agitation or slowing of movements, maintenance of unusual postures.
People with schizophrenia often also experience persistent difficulties with their cognitive or thinking skills, such as memory, attention, and problem-solving.
At least one third of people with schizophrenia experiences complete remission of symptoms (1). Some people with schizophrenia experience worsening and remission of symptoms periodically throughout their lives, others a gradual worsening of symptoms over time.
Magnitude and impact
Schizophrenia affects approximately 24 million people or 1 in 300 people (0.32%) worldwide. This rate is 1 in 222 people (0.45%) among adults (2). It is not as common as many other mental disorders. Onset is most often during late adolescence and the twenties, and onset tends to happen earlier among men than among women.
Schizophrenia is frequently associated with significant distress and impairment in personal, family, social, educational, occupational, and other important areas of life.
People with schizophrenia are 2 to 3 times more likely to die early than the general population (3). This is often due to physical illnesses, such as cardiovascular, metabolic, and infectious diseases.
People with schizophrenia often experience human rights violations both inside mental health institutions and in community settings. Stigma against people with this condition is intense and widespread, causing social exclusion, and impacting their relationships with others, including family and friends. This contributes to discrimination, which in turn can limit access to general health care, education, housing, and employment.
During humanitarian and public health emergencies, extreme stress and fear, breakdown of social supports, isolation and disruption of health-care services and supply of medication can occur. These changes can have an impact on the lives of people with schizophrenia, such as exacerbation of existing symptoms. During emergencies, people with schizophrenia are more vulnerable than others to various human rights violations, including neglect, abandonment, homelessness, abuse and exclusion.
Causes of schizophrenia
Research has not identified one single cause of schizophrenia. It is thought that an interaction between genes and a range of environmental factors may cause schizophrenia. Psychosocial factors may also affect the onset and course of schizophrenia. Heavy use of cannabis is associated with an elevated risk of the disorder.
Currently, the vast majority of people with schizophrenia around the world are not receiving mental health care. Approximately 50% of people in mental hospitals have a schizophrenia diagnosis (4). Only 31.3% of people with psychosis receive specialist mental health care (5). Most resources for mental health services are inefficiently spent on care within mental hospitals.
There is clear evidence that mental hospitals are not effective in providing the care that people with mental health conditions need and, regularly, violate the basic human rights of persons with schizophrenia. Efforts to transfer care from mental health institutions to the community need to be expanded and accelerated. Such efforts start with the development of a range of quality community-based mental health services. Options for community-based mental health care include integration in primary health and general hospital care, community mental health centres, day centres, supported housing, and outreach services for home-based support. The engagement of the person with schizophrenia, family members and the wider community in providing support is important.
Management and support
A range of effective care options for people with schizophrenia exist, and these include medication, psychoeducation, family interventions, cognitive-behavioural therapy and psychosocial rehabilitation (e.g., life skills training). Facilitated assisted living, supported housing and supported employment are essential care options that should be available for people with schizophrenia. A recovery-oriented approach – giving people agency in treatment decisions – is essential for people with schizophrenia and for their families and/or caregivers as well.
WHO response
WHO’s Comprehensive Mental Health Action Plan 2013-2030 highlights the steps required to provide appropriate services for people with mental disorders including schizophrenia. A key recommendation of the Action Plan is to shift services from institutions to the community. The WHO Special Initiative for Mental Health aims to further progress towards objectives of the Comprehensive Mental Health Action Plan 2013-2030 by ensuring 100 million more people have access to quality and affordable care for mental health conditions.
WHO's Mental Health Gap Action Programme (mhGAP) uses evidence-based technical guidance, tools and training packages to expand service in countries, especially in resource-poor settings. It focuses on a prioritized set of conditions, including psychosis, directing capacity building towards non-specialized health-care providers in an integrated approach that promotes mental health at all levels of care. Currently mhGAP is being implemented in more than 100 WHO Member States.
The WHO QualityRights Project involves improving the quality of care and human rights conditions in mental health and social care facilities and to empower organizations to advocate for the health of people with mental health conditions and psychosocial disabilities.
The WHO guidance on community mental health services and person-centred and rights-based approaches provides information and support to all stakeholders who wish to develop or transform their mental health system and services to align with international human rights standards including the UN Convention on the Rights of Persons with Disabilities.
(1) Harrison G, Hopper K, Craig T, Laska E, Siegel C, Wanderling J. Recovery from psychotic illness: a 15- and 25-year international follow-up study. Br J Psychiatry 2001;178:506-17.
(2) Institute of health Metrics and Evaluation (IHME). Global Health Data Exchange (GHDx). http://ghdx.healthdata.org/gbd-results-tool?params=gbd-api-2019-permalink/27a7644e8ad28e739382d31e77589dd7 (Accessed 25 September 2021)
(3) Laursen TM, Nordentoft M, Mortensen PB. Excess early mortality in schizophrenia. Annual Review of Clinical Psychology , 2014;10, 425-438.
(4) WHO. Mental health systems in selected low- and middle-income countries: a WHO-AIMS cross-national analysis. WHO: Geneva, 2009
(5) Jaeschke K et al. Global estimates of service coverage for severe mental disorders: findings from the WHO Mental Health Atlas 2017 Glob Ment Health 2021;8:e27.
WHO’s Comprehensive Mental Health Action Plan 2013-2030
WHO Special Initiative for Mental Health
WHO's Mental Health Gap Action Programme (mhGAP )
WHO QualityRights Project
WHO guidance on community mental health services and person-centred and rights-based approaches
More on mental health
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Research Highlights: Schizophrenia
Schizophrenia is a highly heritable psychiatric disorder characterized by hallucinations, emotional withdrawal, and a decline in cognitive function. Over the past six decades, there has been little innovation in drug development for the disorder, which afflicts roughly one percent of all adults, and currently available medications address only one of the symptoms (psychosis), not the more debilitating cognitive impairments. The molecular and cellular underpinnings of schizophrenia have not been well understood. There are no good models of schizophrenia in cells, animals, or human tissues, so traditional scientific approaches can’t be used to illuminate the disorder.
Scientists in the Stanley Center for Psychiatric Research at Broad Institute develop and employ state-of-the-art genome analysis methods to identify genetic risk factors for schizophrenia and uncover novel biochemical pathways and new targets for drug discovery. Broad scientists continue to collaborate with researchers across the globe to collect genetic material from tens of thousands of patients with schizophrenia and healthy controls. By analyzing these populations, they’ve been able to identify common and rare mutations contributing to schizophrenia risk, shedding light on biological pathways involved.
In July 2014, a multinational, collaborative effort including researchers from the Broad Institute and scores of other institutions across the globe announced results of the largest genomic study published on any psychiatric disorder to date. Published in Nature, the findings of the genome-wide association study (GWAS) describe more than 100 locations in the genome associated with risk of developing schizophrenia, up from only a handful known a few years prior, and point to biological mechanisms and pathways that may underlie the disorder. The study was the result of several years of work by the Schizophrenia Working Group of the Psychiatric Genomics Consortium, an international, multi-institutional collaboration founded in 2007 to conduct broad-scale analyses of genetic data for psychiatric disease.
In January, 2016 a landmark study led by scientists in the Stanley Center, Harvard Medical School, and Boston Children’s Hospital uncovered genetic evidence that schizophrenia may be caused in part by excessive synaptic pruning, or elimination of connections between neurons, in the brain during late adolescence, the typical period of onset for schizophrenia symptoms. This work represented the first time that the disorder was linked by genetic evidence to a specific gene – the immune molecule known as complement component 4 (C4) – and biological process – the elimination of neuronal connections in the developing brain, known as synaptic pruning. Enabled by catalytic philanthropic funding at the Stanley Center, the study suggests that excessive or prolonged synaptic pruning may lead to development of schizophrenia. Read more in the Broad press release or news story.
Schizophrenia news from the Broad
Psychiatric disorders share an underlying genetic basis (June 2018) Psychiatric disorders may have important molecular similarities that are not reflected in current diagnostic categories.
In psychiatric genetics, a push to think globally, act locally (March 2018) Broad researchers are engaged in a massive effort to expand genetic diversity in psychiatric research, and to increase low and middle-income countries' capacity for large-scale research. One of their first stops: Africa.
First glimpse of schizophrenia’s genetic roots shines light on a developmental process gone awry (January 2016) Groundbreaking work is the result of analytical ingenuity, fortuitous collaborations, and catalytic philanthropic funding.
International research institutes team up to build new schizophrenia patient collections (August 2015) Institute for Molecular Medicine Finland (FIMM) at the University of Helsinki and the Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard, together with its international partners, are initiating major new sample collections in several regions and countries. The goal is to collect up to 50,000 samples from schizophrenia patients across the globe.
Stanley Center at the Broad Institute and New York Stem Cell Foundation partner to develop stem cell resource for schizophrenia and psychiatric diseases (February 2015) Induced pluripotent stem cell lines to be made from people with schizophrenia and other psychiatric disorders, to study cell changes.
Study identifies biological mechanisms for schizophrenia, bipolar disorder and depression (January 2015) New research has found that common psychiatric disorders such as schizophrenia, bipolar disorder and major depression share genetic risk factors related to immune function and DNA regulation.
$650 million commitment to Stanley Center at Broad Institute aims to galvanize mental illness research (July 2014) The commitment is aimed at bringing new treatments based on molecular understanding to hundreds of millions of people around the world.
International team sheds new light on biology underlying schizophrenia (July 2014) Genes, pathways identified could inform new approaches to treatment.
New studies show that many rare mutations contribute to schizophrenia risk (January 2014) Scientists analyzed the exomes, or protein-coding regions, of people with schizophrenia and their healthy counterparts, pinpointing the sites of mutations and identifying patterns that reveal clues about the biology underlying the disorder.
Rooting out schizophrenia (August 2013) In one of the largest systematic analyses of schizophrenia to date, researchers from the Broad’s Stanley Center for Psychiatric Research and elsewhere identified 13 new areas of the genome linked to schizophrenia.
Genetic variants for schizophrenia, bipolar disorder identified (September 2011) Two studies combining thousands of patient samples have allowed differences in DNA associated with the diseases to rise above a vast sea of statistical noise.
A rare glimpse of schizophrenia's genetic roots (July 2008) A multinational consortium uncovers some of the first definitive genetic links to schizophrenia and helps to define the diversity of DNA changes that contribute to the disease.
- Frequently Asked Questions
- Nature : Schizophrenia risk from complex variation of complement component 4. [external link]
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News & Research
Biological origin of schizophrenia.
Imaging studies showed C4 (in green) located at the synapses of primary human neurons. Image: Heather de Rivera, McCarroll lab
The risk of schizophrenia increases if a person inherits specific variants in a gene related to “synaptic pruning”—the elimination of connections between neurons—according to a study from Harvard Medical School, the Broad Institute and Boston Children’s Hospital. The findings were based on genetic analysis of nearly 65,000 people.
The study represents the first time that the origin of this psychiatric disease has been causally linked to specific gene variants and a biological process.
Get more HMS news here
It also helps explain two decades-old observations: synaptic pruning is particularly active during adolescence, which is the typical period of onset for symptoms of schizophrenia, and the brains of schizophrenic patients tend to show fewer connections between neurons.
The gene, complement component 4 (C4), plays a well-known role in the immune system. It has now been shown to also play a key role in brain development and schizophrenia risk. The insight may allow future therapeutic strategies to be directed at the disorder’s roots, rather than just its symptoms.
The study, which appears online Jan. 27 in Nature , was led by HMS researchers at the Broad Institute’s Stanley Center for Psychiatric Research and Boston Children’s. They include senior author Steven McCarroll, HMS associate professor of genetics and director of genetics for the Stanley Center; Beth Stevens , HMS assistant professor of neurology at Boston Children’s and institute member at the Broad; Michael Carroll , HMS professor of pediatrics at Boston Children’s; and first author Aswin Sekar , an MD-PhD student at HMS.
The study has the potential to reinvigorate translational research on a debilitating disease. Schizophrenia afflicts approximately 1 percent people worldwide and is characterized by hallucinations, emotional withdrawal and a decline in cognitive function. These symptoms most frequently begin in patients when they are teenagers or young adults.
“These results show that it is possible to go from genetic data to a new way of thinking about how a disease develops—something that has been greatly needed.”
First described more than 130 years ago, schizophrenia lacks highly effective treatments and has seen few biological or medical breakthroughs over the past half-century.
In the summer of 2014, an international consortium led by researchers at the Stanley Center identified more than 100 regions in the human genome that carry risk factors for schizophrenia.
The newly published study now reports the discovery of the specific gene underlying the strongest of these risk factors and links it to a specific biological process in the brain.
“Since schizophrenia was first described over a century ago, its underlying biology has been a black box, in part because it has been virtually impossible to model the disorder in cells or animals,” said McCarroll. “The human genome is providing a powerful new way in to this disease. Understanding these genetic effects on risk is a way of prying open that black box, peering inside and starting to see actual biological mechanisms.”
“This study marks a crucial turning point in the fight against mental illness,” said Bruce Cuthbert , acting director of the National Institute of Mental Health. “Because the molecular origins of psychiatric diseases are little-understood, efforts by pharmaceutical companies to pursue new therapeutics are few and far between. This study changes the game. Thanks to this genetic breakthrough we can finally see the potential for clinical tests, early detection, new treatments and even prevention.”
The path to discovery
The discovery involved the collection of DNA from more than 100,000 people, detailed analysis of complex genetic variation in more than 65,000 human genomes, development of an innovative analytical strategy, examination of postmortem brain samples from hundreds of people and the use of animal models to show that a protein from the immune system also plays a previously unsuspected role in the brain.
Over the past five years, Stanley Center geneticists and collaborators around the world collected more than 100,000 human DNA samples from 30 different countries to locate regions of the human genome harboring genetic variants that increase the risk of schizophrenia. The strongest signal by far was on chromosome 6, in a region of DNA long associated with infectious disease. This caused some observers to suggest that schizophrenia might be triggered by an infectious agent. But researchers had no idea which of the hundreds of genes in the region was actually responsible or how it acted.
Based on analyses of the genetic data, McCarroll and Sekar focused on a region containing the C4 gene. Unlike most genes, C4 has a high degree of structural variability. Different people have different numbers of copies and different types of the gene.
McCarroll and Sekar developed a new molecular technique to characterize the C4 gene structure in human DNA samples. They also measured C4 gene activity in nearly 700 post-mortem brain samples.
They found that the C4 gene structure (DNA) could predict the C4 gene activity (RNA) in each person’s brain. They then used this information to infer C4 gene activity from genome data from 65,000 people with and without schizophrenia.
These data revealed a striking correlation. People who had particular structural forms of the C4 gene showed higher expression of that gene and, in turn, had a higher risk of developing schizophrenia.
Connecting cause and effect through neuroscience
But how exactly does C4—a protein known to mark infectious microbes for destruction by immune cells—affect the risk of schizophrenia?
Answering this question required synthesizing genetics and neurobiology.
Stevens, a recent recipient of a MacArthur Foundation “genius grant,” had found that other complement proteins in the immune system also played a role in brain development. These results came from studying an experimental model of synaptic pruning in the mouse visual system.
“This discovery enriches our understanding of the complement system in brain development and in disease, and we could not have made that leap without the genetics.”
Carroll had long studied C4 for its role in immune disease, and developed mice with different numbers of copies of C4.
The three labs set out to study the role of C4 in the brain.
They found that C4 played a key role in pruning synapses during maturation of the brain. In particular, they found that C4 was necessary for another protein—a complement component called C3—to be deposited onto synapses as a signal that the synapses should be pruned. The data also suggested that the more C4 activity an animal had, the more synapses were eliminated in its brain at a key time in development.
The findings may help explain the longstanding mystery of why the brains of people with schizophrenia tend to have a thinner cerebral cortex (the brain’s outer layer, responsible for many aspects of cognition) with fewer synapses than do brains of unaffected individuals. The work may also help explain why the onset of schizophrenia symptoms tends to occur in late adolescence.
The human brain normally undergoes widespread synapse pruning during adolescence, especially in the cerebral cortex. Excessive synaptic pruning during adolescence and early adulthood, due to increased complement (C4) activity, could lead to the cognitive symptoms seen in schizophrenia.
“Once we had the genetic findings in front of us we started thinking about the possibility that complement molecules are excessively tagging synapses in the developing brain,” Stevens said.
“This discovery enriches our understanding of the complement system in brain development and in disease, and we could not have made that leap without the genetics,” she said. “We’re far from having a treatment based on this, but it’s exciting to think that one day we might be able to turn down the pruning process in some individuals and decrease their risk.”
Opening a path toward early detection and potential therapies
Beyond providing the first insights into the biological origins of schizophrenia, the work raises the possibility that therapies might someday be developed that could turn down the level of synaptic pruning in people who show early symptoms of schizophrenia.
This would be a dramatically different approach from current medical therapies, which address only a specific symptom of schizophrenia—psychosis—rather than the disorder’s root causes, and which do not stop cognitive decline or other symptoms of the illness.
The researchers emphasize that therapies based on these findings are still years down the road. Still, the fact that much is already known about the role of complement proteins in the immune system means that researchers can tap into a wealth of existing knowledge to identify possible therapeutic approaches. For example, anticomplement drugs are already under development for treating other diseases.
“In this area of science, our dream has been to find disease mechanisms that lead to new kinds of treatments,” said McCarroll. “These results show that it is possible to go from genetic data to a new way of thinking about how a disease develops—something that has been greatly needed.”
This work was supported by the Broad Institute’s Stanley Center for Psychiatric Research and by the National Institutes of Health (grants U01MH105641, R01MH077139 and T32GM007753).
Adapted from a Broad Institute news release .
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Treatment - Schizophrenia
Schizophrenia is usually treated with an individually tailored combination of talking therapy and medicine.
Most people with schizophrenia are treated by community mental health teams (CMHTs).
The goal of the CMHT is to provide day-to-day support and treatment while ensuring you have as much independence as possible.
A CMHT can be made up of and provide access to:
- social workers
- community mental health nurses – who have specialist training in mental health conditions
- occupational therapists
- pharmacists
- counsellors and psychotherapists
- psychologists and psychiatrists – the psychiatrist is usually the senior clinician in the team
After your first episode of schizophrenia, you should initially be referred to an early intervention team.
These specialist teams provide treatment and support, and are usually made up of psychiatrists, psychologists, mental health nurses, social workers and support workers.
Care programme approach (CPA)
People with complex mental health conditions are usually entered into a treatment process known as a care programme approach (CPA). A CPA is essentially a way of ensuring you receive the right treatment for your needs.
There are 4 stages to a CPA:
- assessment – your health and social needs are assessed
- care plan – a care plan is created to meet your health and social needs
- key worker appointed – a key worker, usually a social worker or nurse, is your first point of contact with other members of the CMHT
- reviews – your treatment will be regularly reviewed and, if needed, changes to the care plan can be agreed
Not everyone uses the CPA. Some people may be cared for by their GP, while others may be under the care of a specialist.
You'll work together with your healthcare team to develop a care plan. The care plan may involve an advance statement or crisis plan, which can be followed in an emergency.
Your care plan should include a combined healthy eating and physical activity programme and support for giving up smoking, if you smoke.
Your care co-ordinator will be responsible for making sure all members of your healthcare team, including your GP, have a copy of your care plan.
Further information
- Rethink Mental Illness: Care programme approach
Acute episodes
People who have serious psychotic symptoms as the result of an acute schizophrenic episode may require a more intensive level of care than a CMHT can provide.
These episodes are usually dealt with by antipsychotic medication and special care.
Crisis resolution teams (CRT)
A treatment option is to contact a home treatment or crisis resolution team (CRT). CRTs treat people with serious mental health conditions who are currently experiencing an acute and severe psychiatric crisis.
Without the involvement of the CRT, these people would require treatment in hospital.
The CRT aims to treat people in the least restrictive environment possible, ideally in or near their home. This can be in your own home, in a dedicated crisis residential home or hostel, or in a day care centre.
CRTs are also responsible for planning aftercare once the crisis has passed to prevent a further crisis occurring.
Your care co-ordinator should be able to provide you and your friends or family with contact information in the event of a crisis.
Voluntary and compulsory detention
More serious acute schizophrenic episodes may require admission to a psychiatric ward at a hospital or clinic. You can admit yourself voluntarily to hospital if your psychiatrist agrees it's necessary.
People can also be compulsorily detained at a hospital under the Mental Health Act (2007), but this is rare.
It's only possible for someone to be compulsorily detained at a hospital if they have a severe mental disorder and if detention is necessary:
- in the interests of the person's own health and safety
- to protect others
People with schizophrenia who are compulsorily detained may need to be kept in locked wards.
All people being treated in hospital will stay only as long as is absolutely necessary for them to receive appropriate treatment and arrange aftercare.
An independent panel will regularly review your case and progress. Once they feel you're no longer a danger to yourself and others, you'll be discharged from hospital. However, your care team may recommend you remain in hospital voluntarily.
Advance statements
If it's felt there's a significant risk of future acute schizophrenic episodes occurring, you may want to write an advance statement.
An advance statement is a series of written instructions about what you would like your family or friends to do in case you experience another acute schizophrenic episode. You may also want to include contact details for your care co-ordinator.
If you want to make an advance statement, talk to your care co-ordinator, psychiatrist or GP.
Further information
- Mind: Health and social care rights
Antipsychotics
Antipsychotics are usually recommended as the initial treatment for the symptoms of an acute schizophrenic episode. They work by blocking the effect of the chemical dopamine on the brain.
Antipsychotics can usually reduce feelings of anxiety or aggression within a few hours of use, but may take several days or weeks to reduce other symptoms, such as hallucinations or delusional thoughts.
It's important that your doctor gives you a thorough physical examination before you start taking antipsychotics, and that you work together to find the right one for you.
Antipsychotics can be taken orally as a pill, or be given as an injection known as a depot. Several slow-release antipsychotics are available. These require you to have one injection every 2 to 4 weeks.
You may only need antipsychotics until your acute schizophrenic episode has passed.
However, most people take medication for 1 or 2 years after their first psychotic episode to prevent further acute schizophrenic episodes occurring, and for longer if the illness is recurrent.
There are 2 main types of antipsychotics:
- typical antipsychotics – the first generation of antipsychotics developed in the 1950s
- atypical antipsychotics – newer-generation antipsychotics developed in the 1990s
The choice of antipsychotic should be made following a discussion between you and your psychiatrist about the likely benefits and side effects.
Both typical and atypical antipsychotics can cause side effects, although not everyone will experience them and the severity will differ from person to person.
The side effects of typical antipsychotics include:
- muscle twitches
- muscle spasms
Side effects of both typical and atypical antipsychotics include:
- weight gain, particularly with some atypical antipsychotics
- blurred vision
- constipation
- lack of sex drive
Tell your care co-ordinator, psychiatrist or GP if your side effects become severe. There may be an alternative antipsychotic you can take or additional medicines that will help you deal with the side effects.
If you do not benefit from your antipsychotic medicine after taking it regularly for several weeks, an alternative can be tried. It's important to work with your treatment team to find the right medicine for you.
Do not stop taking your antipsychotics without first consulting your care co-ordinator, psychiatrist or GP. If you stop taking them, you could have a relapse of symptoms.
Your medicine should be reviewed at least once a year.
- Mind: Antipsychotics
- Royal College of Psychiatrists: Depot medication
Talking therapies
Talking therapies can help people with schizophrenia cope with the symptoms of hallucinations or delusions better.
They can also help treat some of the negative symptoms of schizophrenia, such as apathy or a lack of enjoyment and interest in things you used to enjoy.
Talking therapies for schizophrenia work best when they're combined with antipsychotic medication.
Common talking therapies for schizophrenia include:
- cognitive behavioural therapy (CBT)
- family therapy
- arts therapy
Cognitive behavioural therapy (CBT)
Cognitive behavioural therapy (CBT) aims to help you identify the thinking patterns that are causing you to have unwanted feelings and behaviour, and learn to change this thinking with more realistic and useful thoughts.
For example, you may be taught to recognise examples of delusional thinking. You may then receive help and advice about how to avoid acting on these thoughts.
Most people require a series of CBT sessions over the course of a number of months. CBT sessions usually last for about an hour.
Your GP or care co-ordinator should be able to arrange a referral to a CBT therapist.
Family therapy
Many people with schizophrenia rely on family members for their care and support. While most family members are happy to help, caring for somebody with schizophrenia can place a strain on any family.
Family therapy is a way of helping you and your family cope better with your condition. It involves a series of informal meetings over a period of around 6 months.
Meetings may include:
- discussing information about schizophrenia
- exploring ways of supporting somebody with schizophrenia
- deciding how to solve practical problems that can be caused by the symptoms of schizophrenia
If you think you and your family could benefit from family therapy, speak to your care co-ordinator or GP.
Arts therapy
Arts therapies are designed to promote creative expression. Working with an arts therapist in a small group or individually can allow you to express your experiences with schizophrenia.
Some people find expressing things in a non-verbal way through the arts can provide a new experience of schizophrenia and help them develop new ways of relating to others.
Arts therapies have been shown to alleviate the negative symptoms of schizophrenia in some people.
The National Institute for Health and Care Excellence (NICE) recommends that arts therapies are provided by an arts therapist registered with the Health and Care Professions Council who has experience of working with people with schizophrenia.
Want to know more?
- Mental Health Foundation: talking therapies
- Mind: talking therapy and counselling
Page last reviewed: 11 November 2019 Next review due: 11 November 2022
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- Published: 12 November 2015
- Schizophrenia
- René S. Kahn 1 ,
- Iris E. Sommer 1 ,
- Robin M. Murray 2 ,
- Andreas Meyer-Lindenberg 3 ,
- Daniel R. Weinberger 4 ,
- Tyrone D. Cannon 5 ,
- Michael O'Donovan 6 ,
- Christoph U. Correll 7 , 8 ,
- John M. Kane 7 , 8 ,
- Jim van Os 9 , 10 &
- Thomas R. Insel 11
Nature Reviews Disease Primers volume 1 , Article number: 15067 ( 2015 ) Cite this article
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- Neuroscience
Schizophrenia is a chronic psychiatric disorder with a heterogeneous genetic and neurobiological background that influences early brain development, and is expressed as a combination of psychotic symptoms — such as hallucinations, delusions and disorganization — and motivational and cognitive dysfunctions. The mean lifetime prevalence of the disorder is just below 1%, but large regional differences in prevalence rates are evident owing to disparities in urbanicity and patterns of immigration. Although gross brain pathology is not a characteristic of schizophrenia, the disorder involves subtle pathological changes in specific neural cell populations and in cell–cell communication. Schizophrenia, as a cognitive and behavioural disorder, is ultimately about how the brain processes information. Indeed, neuroimaging studies have shown that information processing is functionally abnormal in patients with first-episode and chronic schizophrenia. Although pharmacological treatments for schizophrenia can relieve psychotic symptoms, such drugs generally do not lead to substantial improvements in social, cognitive and occupational functioning. Psychosocial interventions such as cognitive–behavioural therapy, cognitive remediation and supported education and employment have added treatment value, but are inconsistently applied. Given that schizophrenia starts many years before a diagnosis is typically made, the identification of individuals at risk and those in the early phases of the disorder, and the exploration of preventive approaches are crucial.
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Acknowledgements
The authors thank H. Schnack, N. E. M. van Haren and H. E. Hulshoff Pol from the University Medical Centre Utrecht for assistance with Figure 4b .
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Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands
René S. Kahn & Iris E. Sommer
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
Robin M. Murray
University of Heidelberg, Central Institute of Mental Health, Mannheim, Germany
Andreas Meyer-Lindenberg
Lieber Institute for Brain Development and Departments of Psychiatry, Neurology, Neuroscience and The Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Daniel R. Weinberger
Department of Psychology, Yale University, New Haven, Connecticut, USA
Tyrone D. Cannon
MRC Centre for Psychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
Michael O'Donovan
Hofstra North Shore-LIJ School of Medicine, Hempstead, New York, USA
Christoph U. Correll & John M. Kane
The Zucker Hillside Hospital, Glen Oaks, New York, USA
Departments of Psychiatry and Psychology, Maastricht University Medical Centre, Maastricht, The Netherlands
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, King's Health Partners, London, UK
US National Institute of Mental Health, Bethesda, Maryland, USA
Thomas R. Insel
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Contributions
Introduction (R.S.K. and I.E.S.); Epidemiology (R.M.M.); Mechanisms/pathophysiology (A.M.-L. and D.R.W.); Diagnosis, screening and prevention (M.O.D. and T.D.C.); Management (C.U.C. and J.M.K.); Quality of life (J.v.O.); Outlook (T.R.I.); Overview of Primer (R.S.K.).
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Correspondence to René S. Kahn .
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J.M.K. has received honoraria for lectures and/or consulting from Alkermes, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, FORUM Pharmaceuticals, Genentech, Intra-Cellular Therapies, Janssen, Johnson and Johnson, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Reviva Pharmaceuticals, Roche and Sunovion Pharmaceuticals. He has received grant support from Genentech, Johnson and Johnson and Otsuka. He is a shareholder of MedAvante and the Vanguard Research Group. T.D.C. is a consultant to the Los Angeles County Department of Mental Health and Boehringer Ingelheim and is a co-inventor on a pending patent for a blood-based predictive biomarker for psychosis. C.U.C. has been a consultant and/or adviser to, or has received honoraria from AbbVie, Actavis, Alkermes, Bristol-Myers Squibb, Eli Lilly, Genentech, the Gerson Lehrman Group, Intra-Cellular Therapies, Janssen Pharmaceuticals, Johnson and Johnson, Lundbeck, MedAvante, Medscape, Otsuka, Pfizer, ProPhase, Reviva Pharmaceuticals, Roche, Sunovion Pharmaceuticals, Supernus Pharmaceuticals and Takeda. He has received grant support from Bristol-Myers Squibb, Otsuka and Takeda. A.M.-L. is a consultant for AstraZeneca, Elsevier, F. Hoffmann-La Roche, the Gerson Lehrman Group, Lundbeck, Outcome Europe Sàrl, Outcome Sciences, Roche Pharma, Servier International and Thieme Verlag. He has held lectures that included the receipt of travel fees for Abbott, AstraZeneca, Aula Médica Congresos, BASF, Groupo Ferrer International, Janssen-Cilag, Lilly Deutschland, LVR Klinikum Düsseldorf, Servier Deutschland and Otsuka. He holds grants from Hans-Jörg Weitbrecht Award, European College of Neuropsychopharmacology (ECNP) Neuropsychopharmacology Award and Prix ROGER DE SPOELBERCH. R.S.K. has served as a member of the Data Safety Monitoring Board (DSMB) for Janssen-Cilag, Otsuka and Sunovion Pharmaceuticals, been consultant to Forrest, Gedeon Richter, FORUM Pharamaceuticals and Roche, and has received speaking fees from AstraZeneca, Eli Lilly and Lundbeck. M.O.D. has received a consultancy fee from Roche. R.M.M. has received honoraria for lectures from Janssen, Lundbeck, Otsuka and Roche. I.E.S., T.R.I., D.R.W. and J.v.O. declare no competing interests.
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Kahn, R., Sommer, I., Murray, R. et al. Schizophrenia. Nat Rev Dis Primers 1 , 15067 (2015). https://doi.org/10.1038/nrdp.2015.67
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DOI : https://doi.org/10.1038/nrdp.2015.67
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