Know Your Brain: Schizophrenia
Devon had been a superstar student in high school, and by the time she was a freshman in college she already had her career path to becoming a physician mapped out. She was intelligent, ambitious, and seemingly destined for success. But by the end of her very first semester at college her life was in complete disarray. She appeared haggard and disheveled, was failing all of her classes, and displayed a paranoid mistrust of everyone around her.
Devon’s transformation began about mid-way through her first semester when she started to lose interest in academics—and everything else, it seemed; sometimes she just wanted to stay in bed all day. At first, she thought she might be suffering from depression, or at least some extreme form of homesickness due to her first prolonged stay away from her family. But she also started to notice that almost anywhere she went on campus people were staring and whispering about her. The whispers were critical—sometimes downright mean—and soon Devon started to hear them all the time, whether she was in earshot of others or not. It seemed to her that she was the focal point of everyone at her school—not only students, but also professors, staff, and visitors.
Devon eventually decided that all of these whispers and surreptitious glances harbored malicious intent. She had come to her university hoping to be recognized for her academic success, but now she began to believe that her professors, school administrators, and fellow students were involved in an intricate plot devised to see her fail. She decided she had been identified by a national surveillance system as someone who posed a threat to a medical system that was desperately attempting to hold onto its male dominance.
After that revelation, Devon’s life began to spiral out of control. She rarely went to class, and she tried to avoid everyone. Thinking her roommate was in on the plot against her, she would often sleep in a secluded corner of the library rather than go back to her dorm room. She refused to eat the potentially poisoned food from the school cafeteria, and she lost over 10 pounds. Classmates often saw her walking across campus with her eyes on the ground, muttering to herself. When her parents came to visit late in the semester, they realized the severity of the situation and checked Devon into the hospital.
Devon was eventually diagnosed with schizophrenia, a potentially severe psychiatric condition that affects about 20 million people throughout the world. Schizophrenia defies a clear and simple definition as it can look very different from one patient to the next. The disorder can involve a number of different symptoms; which symptoms are present varies from case to case.
Clinicians often categorize the symptoms of schizophrenia as positive, negative, or cognitive. Positive symptoms involve the development of a behavior or thought pattern that isn’t normally present in a healthy individual. These include psychosis, which is a disruption in reality that might involve delusional thinking like Devon’s paranoia. Hallucinations are also common; typically, the hallucinations are auditory in nature. Many schizophrenics, for example, hear voices in their heads that can sound as clear as if someone else in the room was talking. The critical whispers Devon heard would fall into this category.
Negative symptoms involve the loss of a behavior or function that is typically seen in a healthy individual. Examples include a lack of motivation that can resemble depression, blunted emotion, difficulty experiencing pleasure, and a decreased desire for social interaction.
Cognitive symptoms are those that affect someone’s ability to think clearly, and might involve deficits in attention, concentration, and/or memory.
Each patient with schizophrenia displays a unique combination of positive, negative, and cognitive symptoms. The diverse presentation (combined with supporting genetic data) has led some to suggest that cases diagnosed as schizophrenia really may represent distinct disorders that are erroneously lumped together in one category.
Schizophrenia and the brain
Given the diverse nature of the condition, perhaps it’s not surprising that it has been difficult to identify specific aspects of brain function that are consistently pathological in schizophrenic patients. A great deal of research over the past half century, however, has focused on neurotransmitter abnormalities at the root of the disorder.
The neurotransmitter dopamine has received a lot of this attention. All of the drugs used to treat schizophrenia act to reduce dopamine activity, and drugs that increase dopamine levels (e.g., amphetamine) can induce behavior that in some ways resembles the psychotic states schizophrenic patients experience. Both of these observations support the hypothesis that schizophrenia is linked to some degree of dopamine dysregulation. There is also evidence that dopamine synthesis and release in the brain is higher than normal in schizophrenic patients.
Although dopamine has received the lion’s share of attention when it comes to neurotransmitter abnormalities in schizophrenia, researchers have also found that attempting to explain the varied symptoms of the disorder with fluctuations in the levels of one neurotransmitter is a somewhat futile task. This is one reason scientists have turned their focus to other neurotransmitter systems as well. The activity of the neurotransmitter glutamate, for example—a widespread, primarily excitatory, neurotransmitter—seems to also be dysregulated in schizophrenic patients. Some researchers think these glutamate abnormalities might be especially capable of accounting for the negative and cognitive symptoms of schizophrenia—symptoms that dopamine irregularities have been less successful in explaining.
Thus, it may be that dopamine abnormalities are more responsible for positive symptoms like delusions and hallucinations, while glutamate abnormalities contribute more to negative symptoms. A case of schizophrenia, then, could potentially involve abnormalities in both dopamine and glutamate activity, and some hypotheses suggest that altered glutamate signaling may lead to abnormalities in dopamine signaling.
Although they tend to get less research attention, other neurotransmitters like GABA, serotonin, and norepinephrine have been implicated as well, further complicating the picture.
Despite decades of research, we are left with many questions about how these neurotransmitter abnormalities translate into schizophrenia symptoms. In other words, even if we can say with some confidence that dopamine and/or glutamate activity is dysregulated in schizophrenia, researchers are still trying to figure out how these neurotransmitter irregularities might lead to the diverse symptoms of the disorder. Thus, overall findings about abnormalities in neurotransmitter activity have been difficult to translate into a model that helps to explain the complex symptomatology of schizophrenia.
Neurodevelopmental origins and risk factors of schizophrenia
And then there is the question of what causes schizophrenia to emerge in the first place. The general thinking in this respect is that schizophrenia has its origins in early neural development, when a brain that is particularly susceptible—due perhaps to genetic makeup—experiences some insult while still in the womb. This fetal stress might alter neural development and subsequent brain function in a way that increases the likelihood of developing schizophrenia later in life. Why it would take a couple decades for that fetal stress to manifest into a psychiatric condition, however, is still unclear.
In support of this neurodevelopmental perspective, there is evidence that genetics makes a substantial contribution to the development of schizophrenia, and many of the genes that have been implicated in schizophrenia are also thought to play an important role in fetal development. Additionally, complications during pregnancy or delivery and indicators of abnormal fetal development like low birth weight are also considered risk factors for developing schizophrenia later in life. And babies who are born in late winter and spring have a slightly increased risk of developing schizophrenia, which some have suggested may be linked to an increased likelihood of maternal respiratory infections or malnutrition (e.g., vitamin D deficiency) during the winter.
There are a number of other risk factors for schizophrenia, but their mechanistic connection to the condition has not been clearly established. For example: older fathers are more likely to have a child who develops schizophrenia, males are more likely to develop schizophrenia than females, higher rates of schizophrenia are found in urban environments, migrant populations have a greater risk of schizophrenia, childhood adversity like physical abuse or sexual abuse has been linked to schizophrenia, and drug abuse (e.g., heavy cannabis use) has been linked to an increased risk of schizophrenia.
The most common treatment for schizophrenia since the middle of the 20th century has been the use of antipsychotic drugs. Chlorpromazine, the first antipsychotic, was developed in the 1950s; since then, a long list of similar antipsychotic drugs have been brought to market. These drugs have an important mechanistic similarity in that they all act to block dopamine receptors to some degree. While antipsychotic drugs are relatively effective in reducing positive symptoms, however, they demonstrate little benefit in treating negative symptoms (which are often more functionally impairing than positive symptoms). And, many patients do not respond to antipsychotic drugs at all.
Additionally, antipsychotic drugs have a problematic side effect profile. The dopamine receptor blockade caused by the drugs can lead to a number of side effects, including movement-related problems such as Parkinsonism (characterized by tremors, slow movement, rigidity, and postural impairments), dystonia (characterized by sustained involuntary muscle contractions, repetitive abnormal movements or fixed postures), akathisia (characterized by restlessness and an inability to sit still), and tardive dyskinesia (characterized by involuntary, repetitive movements). Tardive dyskinesia can persist even after the patient has stopped taking the drug; indeed, it is sometimes irreversible.
Newer drugs have been touted as being less likely to cause movement-related side effects, but no antipsychotic has been able to fully distance itself from this side effect profile. Additionally, newer antipsychotics (typically referred to as second-generation antipsychotics) have been linked to other problems like weight gain, diabetes, and cardiovascular complications. Thus, treatments for schizophrenia are less than ideal; researchers hope that a better understanding of the disorder will one day lead to improved therapeutic options.
References (in addition to linked text above):
Kahn RS, Sommer IE, Murray RM, Meyer-Lindenberg A, Weinberger DR, Cannon TD, O'Donovan M, Correll CU, Kane JM, van Os J, Insel TR. Schizophrenia. Nat Rev Dis Primers. 2015 Nov 12;1:15067. doi: 10.1038/nrdp.2015.67. PMID: 27189524.
Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet. 2016 Jul 2;388(10039):86-97. doi: 10.1016/S0140-6736(15)01121-6. Epub 2016 Jan 15. PMID: 26777917; PMCID: PMC4940219.