Jyoti Kinghorn 
Schizophrenia treatments may be on the cusp of a seismic shift as new approaches to treat the disease do well in clinical trials and more information becomes available about genetic risk factors.
Schizophrenia is a mental disorder in which a person loses touch with reality. People can hallucinate- seeing, hearing, smelling, and feeling things that are not there. They can have delusions where they fervently believe in something that is not true. They can have abnormal and disorganized speech and movement patterns, and may not be able to care for themselves or live independently. Schizophrenia can also have negative symptoms, such as lack of energy, motivation, and lack of facial expressions.
Antipsychotic medicines have helped many people who suffer from schizophrenia. These medications have helped symptoms reduce in over 70% of the people who stayed on treatment decades after their first diagnosis. About 50% of schizophrenia patients on antipsychotic medicines can get better enough to hold a job and live independently.
However, antipsychotic medicines can have strong side effects, which make some patients stop taking them. There is an urgent need for new therapies that can help patients who do not respond to or cannot tolerate the currently available antipsychotics. Hope may be on the horizon as new drugs enter the market, and scientists discover new genetic risk factors for schizophrenia.
Problems with traditional schizophrenia therapies
Most of the traditional schizophrenia therapies target the dopamine D2 receptors. The dopamine D2 receptors are found in many different areas of the brain and regulate key physiological processes such as cognition, learning, memory, locomotion, attention, sleep, and motivation. Antipsychotic drugs that target the dopamine D2 receptors are based on the theory that most of the “positive symptoms” of schizophrenia such as hallucinations, delusions, and disorganized speech and movements could be caused by an overactive dopamine system. Therefore, partially blocking the dopamine system could reduce the worst effects of schizophrenia.
First-generation antipsychotics such as Adasuve, fluphenazine, and Haldol partially block the dopamine D2 receptors. While these help with the positive symptoms of schizophrenia, they don’t help with the negative symptoms such as reduced emotional expression and lack of motivation.
Second-generation antipsychotics such as risperidone, olanzapine, aripiprazole, and clozapine affect a wider range of neurotransmitter systems and tend to block both dopamine and serotonin receptors. The dopamine D2 receptor and 5-HT2A subtype of serotonin receptors are frequently targeted. Serotonin receptors affect virtually all major organ systems and body functions, including the cardiovascular, gastrointestinal, and central nervous systems. These medications are also effective for the positive symptoms of schizophrenia.
Both first- and second-generation antipsychotics can have adverse side effects.
Some unpleasant side effects include tremors, slowed movements, and uncontrollable facial movements, though these are less prominent with second-generation antipsychotics. Some people on second-generation antipsychotics may experience sluggishness, drowsiness, weight gain, and possibly the onset of diabetes.
Some studies have linked long-term use of antipsychotics with a reduction of brain volume. However, schizophrenia also causes a reduction in brain volume, so more thorough studies were needed to ascertain if the adverse effects in brain volume were due to the medication or the disease. To address these concerns, an international consortium of experts was convened who studied randomized controlled trials. They found that antipsychotics strongly support the treatment of psychosis and improve a patient’s long-term outcomes.
But patients can feel bothered by the side effects enough that they may start skipping doses or stop taking their medication altogether. Discontinuation of antipsychotic drugs can have severe withdrawal symptoms, and increase the likelihood of relapse and worse long-term outcomes.
Therefore, new therapies are needed that have reduced or milder side effects, and increased efficacy at treating both positive and negative symptoms of schizophrenia.
New drugs for schizophrenia
Earlier this year, the FDA approved Teva Pharmaceuticals and MedinCell’s Uzedy (risperidone) extended-release injectable suspension. This is a new long-lasting formulation that only needs to be taken every 4 to 8 weeks and uses a special chemical to ensure steady release of the medication in the body over time. This drug is a second-generation antipsychotic and works through the D2 dopamine receptors and 5-HT2A serotonin receptors. According to clinical trials, Uzedy can reduce the risk of relapse by 80% compared to placebo. The drug also appears to be tolerated well and has a good safety profile.
Another drug called KarXT is currently going through the review process to get FDA approval. Developed by Karuna Therapeutics, this drug is novel in that it does not target dopamine receptors used by most other antipsychotic medications. Instead, KarXT targets the brain’s muscarinic neurotransmitter system.
The muscarinic receptor proteins are found in the brain, spinal cord, and autonomic ganglia. They play critical roles in regulating functions such as cognition, learning, and memory. They also regulate breathing, heart rate, and glandular secretion. The manufacturers have combined the medication with another compound that blocks the activation of muscarinic receptors outside the brain. The results from clinical trials are promising, and the drug may be able to help with both positive and negative symptoms of schizophrenia. It may also be able to help the subset of schizophrenia patients who cannot tolerate or do not respond to medications that target the dopamine receptors. Additional clinical trials for the drug are ongoing.
Including KarXT, there are at least 7 other drugs currently in various stages of clinical trials. Depending on the results, there may be new therapies coming in the following years that have better efficacy, tolerability, and safety profile for schizophrenia patients.
Understanding genetic risk factors
Our knowledge about the genetic risk factors affecting mental disorders is expanding. Scientists are increasingly able to pinpoint genomic regions and specific genes that may increase a person’s chances of developing schizophrenia and other related conditions such as bipolar disorder and schizoaffective disorder. For example, a gene called AKAP11 was found to be a strong risk factor for schizophrenia and bipolar disorder. Genes such as C4 are expressed at higher levels in those with schizophrenia compared to healthy individuals.
One day, the knowledge of genetic risk factors may be used to help those with schizophrenia. Drugs may be developed that could mute the effect of genes that are expressed too much in the schizophrenic condition, or those that enhance the effect of genes that are not expressed enough. Gene therapy approaches may also be developed. However, these studies are in their infancy and experts say that it can take anywhere between 5 and 50 years for the genetic findings to translate into drugs or practices that can affect clinical outcomes.
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