Many psychiatric illnesses, including bipolar disorder, schizophrenia, autism, attention deficit hyperactivity disorder (ADHD), and anxiety disorders may stem from abnormalities in brain development that begin before birth. Researchers are trying to determine whether dietary supplements taken by pregnant mothers or infants can reduce the risk of such illnesses. At a recent scientific meeting, researcher Randal Ross and colleagues reported that compared to placebo, choline supplements reduced problems with a brain process called sensory gating in one-month-old infants and also improved the children’s attention span and social skills at age 3.
Sensory gating is the process by which the brain filters out unimportant information, to avoid flooding higher cortical centers with irrelevant stimuli. Deficits in the way the brain inhibits response to this type of irrelevant information are associated with mental illnesses such as schizophrenia.
In Ross’s study, healthy pregnant mothers received either a placebo or 6300 mg of choline, a nutrient found in liver, egg yolks, and meat. After delivery, the infants also received 700 mg of supplemental choline per day. In children who carried CHRNA7, a risk gene for schizophrenia discovered by Ross’s colleague Robert Freedman, choline reversed the associated risk of sensory gating problems and normalized their behavior at age 3.
People with disorders on the schizophrenia spectrum often suffer cognition problems that affect skills such as the processing of information about people and social situations (social cognition) and the execution of plans (executive function). At the 2015 meeting of the Society for Biological Psychiatry, researcher Larry J. Siever reported that the drug guanfacine improved these types of thinking in people with disorders on the schizophrenic spectrum compared to placebo. Participants were enrolled in a 7.5-week training program to improve cognition.
A gene that plays a role in the pruning of synapses has been linked to schizophrenia. The gene encodes an immune protein called complement component 4 (C4), which may mediate the pruning of synapses, the connections between neurons. Researchers led by Aswin Sekar found that in mice, C4 was responsible for the elimination of synapses. The team linked gene variants that lead to more production of C4A proteins to excessive pruning of synapses during adolescence, the period during which schizophrenia symptoms typically appear. This may explain why the brains of people with schizophrenia have fewer neural connections. The researchers hope that future therapies may target the genetic roots of the illness rather than simply treating its symptoms.
The long-acting aripiprazole is administered every 4 to 6 weeks as an injection in the arm or buttocks. The company announced that it would begin releasing the drug immediately. The drug preparation for maintenance treatment is named Maintena while the preparation for acute treatment is named Aristada.
Researcher Stephanie Ameis reported at the 2015 meeting of the American Academy of Child and Adolescent Psychiatry that following repeated transcranial magnetic stimulation (rTMS), a treatment in which a magnetic coil placed over the scalp delivers electric pulses to the brain, children with schizophrenia and autism spectrum disorders showed improvements in executive function, including working memory. The rTMS treatment targeted the left dorsolateral prefrontal cortex.
In late 2015, the Food and Drug Administration approved the new atypical antipsychotic drug cariprazine for the treatment of schizophrenia and mania in adults. The approval followed a series of clinical trials that showed that the drug reduced symptoms of each illness compared to placebo.
The most common side effects of cariprazine reported in the trials included tremor, slurred speech, and involuntary muscle movements.
In boys, a decrease in the thickness of the cortex is a part of normal maturation. However, according to a recent study, this process is sped up in boys at high risk for schizophrenia when they use marijuana before the age of 16.
Early use of marijuana has been linked to subsequent development of schizophrenia. Schizophrenia begins about 5 years earlier in males than in females, and the male brain goes through more structural changes during adolescence.
A 2015 article by Tomáš Paus in the journal JAMA Psychiatry incorporated data from three studies, which took place in parts of Canada and England and eight European cities. The studies all included magnetic resonance imaging (MRI) scans of the participants, a measure of their genetic risk of developing schizophrenia, and questions about their past marijuana use. In boys at high risk for schizophrenia based on their genetic profile, cortical thickness dropped more among the ones who used high amounts of marijuana before the age of 16 compared to those who did not.
Paus hypothesizes that the development of schizophrenia is a “two-hit process.” People who develop schizophrenia may have an early risk factor, such as their genetic profile or a problem that occurs in utero, and a later stressor such as drug use in adolescence.
N-acetylcysteine (NAC), an antioxidant available without a prescription in health food stores, has shown remarkable effectiveness when added to regular treatments for schizophrenia, bipolar disorder, and the substance abuse that often accompanies these illnesses.
A 2008 article by Michael Berk and colleagues in the journal Biological Psychiatry reported that compared to placebo, 2 grams/day of NAC reduced both positive symptoms of schizophrenia (hallucinations, delusions) and negative symptoms (social withdrawal, difficulty planning and problem-solving). A 2013 study by Mehdi Farokhnia found that 2 grams/day of NAC improved negative symptoms in 42 patients with schizophrenia. Two other studies found that NAC improved deficits in auditory sensory processing in people with schizophrenia.
NAC also improves symptoms of bipolar disorder. A 2008 study by Berk and a 2011 study by Pedro Vieira da Silva Magalhães showed that NAC improved bipolar depression, and a small 2013 study by Magalhães showed that it improved mania in 15 patients. After 24 weeks, 60% of those who took NAC were in remission, compared to 15% of those taking placebo.
NAC is also effective at reducing habitual behaviors such as substance abuse, which is common in patients with schizophrenia and bipolar disorder. Studies have shown that NAC can reduce patients’ use of marijuana, cocaine, alcohol, and nicotine. It is relatively safe with minimal side effects, and fights oxidative stress, which is also common in severe mental illness.
NAC comes in 500mg or 600mg capsules. Dosing typically begins with one capsule twice a day for a week, followed by two tablets twice a day thereafter. As with any recommendations in the BNN, these should not be acted on without guidance from a treating physician.
A 2016 study by Peter S. Bloomfield and colleagues in the American Journal of Psychiatry used PET scans to compare the activity of microglia, immune cells in the central nervous system, in healthy controls, people with schizophrenia, and those at high risk for the illness. It found that both people with schizophrenia and those at high risk had greater brain inflammation than the healthy controls.
The study was the first to show that microglial activity was elevated in people at high risk (who showed some preliminary symptoms of schizophrenia). The finding had a large effect size.
Microglial activity was also correlated with symptom severity in the high-risk participants. Increased microglial activity was not linked to depression, suggesting that it is specific to the development of psychosis.
These findings resemble those of other recent studies showing increased inflammation in people at high risk for psychosis.
The study suggests that increased microglial activity occurs before a first episode of psychosis. That means it could help identify people who may develop schizophrenia. The findings also suggest that anti-inflammatory treatment could theoretically be used to prevent psychosis.
By the time psychosis appears in someone with schizophrenia, biological changes associated with the illness may have already been present for years. A 2015 article by R.S. Kahn and I.E. Sommer in the journal Molecular Psychiatry describes some of these abnormalities and how treatments might better target them.
One such change is in brain volume. At the time of diagnosis, schizophrenia patients have a lower intracranial volume on average than healthy people. Brain growth stops around age 13, suggesting that reduced brain growth in people with schizophrenia occurs before that age.
At diagnosis, patients with schizophrenia show decrements in both white and grey matter in the brain. Grey matter volume tends to decrease further in these patients over time, while white matter volume remains stable or can even increase.
Overproduction of dopamine in the striatum is another abnormality seen in the brains of schizophrenia patients at the time of diagnosis.
Possibly years before the dopamine abnormalities are observed, underfunctioning of the NMDA receptor and low-grade brain inflammation occur. These may be linked to cognitive impairment and negative symptoms of schizophrenia such as social withdrawal or apathy, suggesting that there is an at-risk period before psychosis appears when these symptoms can be identified and addressed. Psychosocial treatments such as individual, group, or family psychotherapy and omega-3 fatty acid supplementation have both been shown to decrease the rate of conversion from early symptoms to full-blown psychosis.
Using antipsychotic drugs to treat the dopamine abnormalities is generally successful in patients in their first episode of schizophrenia. Use of atypical antipsychotics is associated with less brain volume loss than use of the older typical antipsychotics. Treatments to correct the NMDA receptor abnormalities and brain inflammation, however, are only modestly effective. (Though there are data to support the effectiveness of the antioxidant n-acetylcysteine (NAC) on negative symptoms compared to placebo.) Kahn and Sommer suggest that applying treatments when cognitive and social function begin to be impaired (rather than waiting until psychosis appears) could make them more effective.
The authors also suggest that more postmortem brain analyses, neuroimaging studies, animal studies, and studies of treatments’ effects on brain abnormalities are all needed to clarify the causes of the early brain changes that occur in schizophrenia and identify ways of treating and preventing them.