Imagine being diagnosed with a severe mental illness — one that causes you to hear voices that aren’t really there or to see things that no one else can see — and then being told that there are no medications, interventions or treatments that are going to cure you. This is a reality for some people living with schizophrenia, a severe and disabling mental illness that affects about 1 percent of the population.
Although several treatment options (e.g., antipsychotic medications, psychosocial interventions, psychotherapy, etc.) are available to assist patients in managing their symptoms and improving their ability to function, many patients do not achieve full remission from their symptoms. While antipsychotic medications effectively reduce the positive symptoms of schizophrenia (hallucinations, delusions etc.), they are ineffective for reducing the cognitive impairments and negative symptoms.
For this reason, researchers have explored alternative targets for developing treatments in hopes of providing a reduction of a wider range of symptoms for people with schizophrenia. The allosteric control of metabotropic glutamate 2 (mGlu2) receptors has been suggested to be a promising strategy for the treatment of schizophrenia.
Metabolic Glu2 receptors are widely expressed in the brain, especially in regions implicated in schizophrenia, including the prefrontal cortex, hippocampus, striatum, thalamus and amygdala. These glutamate 2 receptors bind to and activate G-proteins and then activate secondary messengers. It has been hypothesized that both serotonin (5-HT2A) and glutamate 2 receptors regulate the release of glutamate and are involved in producing symptoms of psychosis.
A recent analysis of schizophrenia patients’ postmortem brains suggested that lower glutamate signaling may be responsible for the dysfunction. Javier González-Maeso, Ph.D., and his colleagues from the Virginia Commonwealth University, found lower glutamate receptor signaling in the frontal cortex of schizophrenic patients’ postmortem brains. Thus, the researchers argued that when mGlu2 receptors become activated, this may attenuate the cognitive symptoms of schizophrenia and possibly prevent neurodegeneration.
Symptoms of schizophrenia
Schizophrenia is a chronic illness that affects people throughout their lives. The positive symptoms of schizophrenia reflect an excess of normal functions and include hallucinations, delusions, and disorganized speech and behavior. Many people with schizophrenia hear voices (i.e., auditory hallucinations), but any of the senses can be affected, causing people with this illness to see, hear, smell, taste or feel things that aren’t really there. Other positive symptoms include disorganized speech or behavior, and delusions (i.e., false beliefs), which may cause people to believe that someone is trying to control their thoughts, read their minds or is plotting to harm or kill them or their loved ones, which can be both frightening and upsetting to people with the illness as well as to other people around them.
On the other hand, negative symptoms reflect deficits in functioning such as poor grooming and hygiene, limited eye contact, flattened affect (reduced range of emotions), apathy, anhedonia (reduced ability to experience pleasure), social withdrawal, avolition (reduced desire or motivation), and attention and memory problems. Lastly, cognitive symptoms of schizophrenia can overlap with the positive and negative symptoms of the disorder. Some of the common cognitive symptoms include impairments in the ability to produce spontaneous speech (i.e., verbal fluency) and impairments in executive functioning (e.g., problems with attention, concentration, prioritizing and modulating social behavior).
The dopamine hypothesis of schizophrenia
The mesolimbic dopamine pathway and excessive neurotransmission of dopamine were originally proposed to underlie the development and symptoms of schizophrenia. The dopamine hypothesis of schizophrenia proposed that the overactivity of the mesolimbic dopamine pathway was specifically responsible for the development of schizophrenia due to the production of too much dopamine in the brain. Older “typical” antipsychotic medications, such as chlorpromazine and haloperidol, target the excess of dopamine that was believed to be responsible for positive (i.e., hallucinations, delusions, disorganized speech and behavior) schizophrenia symptoms.
Typical antipsychotic medications are considered to be high-affinity antagonists of dopamine D2 receptors, and interfere with dopaminergic neurotransmission in the limbic system and cerebral cortex to reduce dopamine and, consequently, alleviate the positive symptoms of schizophrenia. While typical antipsychotics are considered to be effective for reducing positive symptoms, they are associated with several negative side effects (e.g., hyperprolactinemia) and are limited in reducing negative symptoms and cognitive impairments related to schizophrenia, which contribute to poor prognosis and various functional problems among patients.
The serotonin hypothesis of schizophrenia
Newer, “atypical” antipsychotic medications (e.g., clozapine, risperidone) were introduced as an alternative to typical antipsychotics, as these drugs are less likely to cause the negative side effects caused by typical antipsychotics. Atypical antipsychotics have less affinity for D2 receptors compared to older, typical antipsychotics, but interact more with monoaminergic receptors such as the serotonin 2A receptor (5-HT2A) to influence levels of dopamine.
Due to the action of atypical antipsychotics on increasing serotonin (i.e., 5-hyroxytryptamine or 5-HT2A), researchers proposed the serotonin deficiency hypothesis. This hypothesis suggests that too little serotonin (5-hyroxytryptamine or 5-HT2A) production is involved in the etiology and pathophysiology of schizophrenia.
Despite the effectiveness of atypical antipsychotics in reducing a wider range of symptoms, these medications are only moderately effective in reducing negative symptoms of schizophrenia and are not more effective than older antipsychotics in improving neurocognition. Atypical antipsychotics such as clozapine are also not without side effects — they can lead to metabolic and other severe side effects such as agranulocytosis (a deficiency of white blood cells called granulocytes, or neutrophils, in the blood), which increases an individual’s susceptibility for infection.
Fewer than 35 percent of people with schizophrenia achieve a full remission when treated with typical and atypical antipsychotics, and those who do respond to antipsychotics only achieve partial responsiveness, said González-Maeso and his colleagues from Mount Sinai and Virginia Commonwealth University. In addition, many people taking antipsychotics do not receive any relief for their negative and cognitive symptoms, which can continue to have a significant impairment on their ability to function in their daily lives. The inability of antipsychotics to reduce negative and cognitive symptoms suggests that serotonin and dopamine signaling cannot fully account for the underlying pathology of schizophrenia.
Alternative treatment target for schizophrenia: Glutamate
Over the last 50 years, the pharmacological treatments for schizophrenia have remained unchanged, despite their ineffectiveness in reducing some of the most debilitating symptoms of the disorder. A growing body of evidence suggests that amino acid neurotransmitters (i.e., brain chemicals) such as glutamate (Glu) and γ-amino-butyric acid (GABA), specifically in the hippocampus and prefrontal lobe in the cortex, may play a role in schizophrenia. Specifically, glutamatergic dysfunction may play a role in the cognitive deficits as well as the positive and negative symptoms of schizophrenia.
Glutamatergic theories suggest that the decreased function or dysfunction of N-methyl-aspartate (NMDA) receptors make GABA less effective in inhibiting glutamatergic neurotransmission, which results in the production of too much glutamate and overstimulates the dopamine mesolimbic pathway. It has been proposed that the negative and cognitive symptoms of schizophrenia arise from this over-production of glutamate. Additionally, the resulting excess glutamate might be the underlying process responsible for the structural brain changes seen in patients with schizophrenia.
Treatment is usually a lifelong process for people with schizophrenia that involves a combination of medications, such as antipsychotic medications to help reduce the frequency and severity of symptoms, as well as cognitive behavioral therapy (CBT), family psychoeducation and support, and other psychosocial interventions to help them find employment, housing, self-help groups and crisis support.
Sovereign Health of California offers comprehensive behavioral health treatment services for people with schizophrenia and other mental disorders. Evidence-based treatments are also provided to patients with substance use problems and co-occurring disorders. To find out more about Sovereign Health’s treatment programs available for people who have schizophrenia, please contact our 24/7 helpline to speak to a member of our team.
About the author
Amanda Habermann is a writer for the Sovereign Health Group. A graduate of California Lutheran University, she received her M.S. in clinical psychology with an emphasis in psychiatric rehabilitation. She brings to the team her background in research, testing and assessment, diagnosis and recovery techniques. For more information and other inquiries about this article, contact the author at email@example.com.
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