What is SCHIZOPHRENIA?
Bhavya Pratap Singh, Farooq Ali Khan, Abhishek Kumar, Raamesh Gowri Raghavan, ramachandran. ravishankar, and Sukant Khurana
INTRODUCTION
Schizophrenia is a chronic disease and a severe mental disorder that affects how a person thinks, feels and behaves. People with schizophrenia may seem like they have lost touch with reality characterized by abnormal social behavior and failure to understand what is real.
AFFECTED POPULATION
# This disease begins in early adulthood, between the ages of 15 to 25. It has been found that this disease is more probable in male than in females.
Most males become ill between 16–25 years of age while most females develop symptoms several years later and the incidence in women is noticeably higher in women after age 30. [1]
# In 2017, an estimated 17,000 people worldwide died from behavior related to, or caused by, schizophrenia.
About 0.3–0.7% of people globally are affected during their lifetimes.
Therefore, average frequency of occurrence of disease is about 0.5% globally. These rates are generally similar from country to country excluding few variations. [2]
# The prevalence rate for schizophrenia is approx. 1.1% of the population over the age of 18, including:
1. 6–12 million people in China.
2. 4.3–8.7 million people in India
3. 2.2 million in USA
4. 285,000 people in Australia
5. Over 280,000 people in Canada
6. Over 250,000 diagnosed cases in Britain. [3]
# This disease occurs in all societies regardless of class, colour, religion, culture- however there are some variations in terms of incidence and outcomes for different group of people. [2]
# Some famous personalities which have been affected by schizophrenia are-
1. Tom Harrell ( a Jazz musician )
2. John Nash ( a Mathematician and a Nobel Prize winner )
3. Eduard Einstein ( Albert Einstein’s son )
SYMPTOMS
Some of the common symptoms of the disease are listed below:
1. Patients may suffer from hallucinations. Most reported hallucination is hearing strange voices.
2. They may experience delusions which are often more bizarre or prosecutor in nature.
3. Patients may present disorganized thinking or speech.
4. There is a social withdrawal, sloppiness of dress and hygiene. Loss of motivation and judgement are all common in this disease.
5. Patients may present an unusual phenomena called passivity phenomena. A person starts believing thoughts that are being inserted into his/her mind.
6. They may have difficulties in working and long-term memory, attention, executive functioning and speed of processing.
7. There is often seen a very high rate of irritable bowel syndrome but they often do not mention it unless specifically asked. Psychogenic polydipsia or excessive fluid intake in the absence of psychological reasons to drink, is relatively common in people with schizophrenia.
Schizophrenic symptoms are often described as Positive and Negative symptoms.
Positive symptoms are those that most individuals do not normally experience, but are present in people with schizophrenia. They can include delusions, disordered thoughts and speech, and tactile, auditory, visual, olfactory and gustatory hallucinations, typically regarded as manifestations of psychosis. Positive symptoms generally respond well to medication.
On the other hand, negative symptoms are deficits of normal emotional responses or of other thought processes, and are less responsive to medication. They commonly include flat expressions or little emotion, poverty of speech, inability to experience pleasure, lack of desire to form relationships, and lack of motivation. Negative symptoms appear to contribute more to poor quality of life, functional ability, and the burden on others than positive symptoms do. People with greater negative symptoms often have a history of poor adjustment before the onset of illness, and response to medication is often limited.
DIAGNOSIS
Schizophrenia is often diagnosed by two different criteria i.e. DSM 5 or ICD-10. These criteria use the self-reported experiences of the person and reported abnormalities in behavior, followed by a clinical assessment by a mental health professional.
# DSM 5[4] — In 2013, American Psychiatric Association (APA) released 5th edition of DSM diagnostic tool. Under this, diagnostic criteria have to be met over much of the time of a period of at least one month, with a significant impact on social or occupational functioning for at least six months. The person had to be suffering from delusions, hallucinations, or disorganized speech. A second symptom could be negative symptoms, or severely disorganized or catatonic@ behavior. An assessment covering eight domains of psychopathology — such as whether hallucination or mania is experienced — is recommended to help clinical decision-making. [4]
# ICD-10[5] — ICD-10 criteria are typically used in European countries. This criteria put more emphasis on Schneiderian first-rank symptoms. @
If signs of disturbance are present for more than a month but less than six months, the diagnosis of schizophreniform disorder is applied. Psychotic symptoms lasting less than a month may be diagnosed as brief psychotic disorder, and various conditions may be classed as psychotic disorder not otherwise specified, while schizoaffective disorder is diagnosed if symptoms of mood disorder are substantially present alongside psychotic symptoms. Schizophrenia is not diagnosed if symptoms of pervasive developmental disorder are present unless prominent delusions or hallucinations are also present.
ETIOLOGY OF THE DISEASE
A combination of genetic and environmental factors play a role in the development of schizophrenia.
Genetic Role — Many genes are believed to be involved in schizophrenia, each of small effect and unknown transmission and expression. Many possible candidates have been proposed, including specific copy number variations, NOTCH4@, and histone protein loci. A number of genome-wide associations such as zinc finger protein 804A@ have also been linked. Evidence is emerging that the genetic architecture of schizophrenia involved both common and rare risk variation.
Environmental Role — Environmental factors associated with the development of schizophrenia include the living environment, drug use, and prenatal stressors.
Parenting style seems to have no major effect, although people with supportive parents do better than those with critical or hostile parents. Childhood trauma, death of a parent, and being bullied or abused increase the risk of psychosis. Living in an urban environment during childhood or as an adult has consistently been found to increase the risk of schizophrenia by a factor of two, even after taking into account drug use, ethnic group, and size of social group. Other factors that play an important role include social isolation and immigration related to social adversity, racial discrimination, family dysfunction, unemployment, and poor housing conditions.
It has been hypothesized that in some people, development of schizophrenia is related to intestinal tract dysfunction such as seen with non-celiac gluten sensitivity@ or abnormalities in the intestinal flora. A subgroup of persons with schizophrenia present an immune response to gluten different from that found in people with celiac, with elevated levels of certain serum biomarkers of gluten sensitivity such as anti-gliadin IgG or anti-gliadin IgA antibodies.
Certain drugs like Cannabis, Amphetamines etc. may lead to schizophrenia if the person is exposed to these drugs at an early stage.
Developmental stresses during pregnancy may enhance the effect of schizophrenia in babies. Such stresses may include infections of Chlamydia or Toxoplasma, malnutrition, hypoxia etc.
MECHANISMS
Many have proposed different mechanisms on schizophrenia but most common one is dopamine hypothesis.
According to this model, the symptoms are due to the hyperactive dopaminergic signal transduction. The model draws evidence from the observation that a large number of antipsychotics have dopamine-receptor antagonistic effects. The theory, however, does not posit dopamine overabundance as a complete explanation for schizophrenia. Rather, the overactivation of D2 receptors, specifically, is one effect of the global chemical synaptic dysregulation observed in this disorder. [6]
Interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in schizophrenia, largely because of the abnormally low levels of glutamate receptors found in the postmortem brains of those diagnosed with schizophrenia, and the discovery that glutamate-blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition. Reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function, and glutamate can affect dopamine function, both of which have been implicated in schizophrenia.[7]
MEDICATIONS
The primary treatment for schizophrenia is psychological counseling and anti-psychotic drugs.
The choice of drugs may depend on its benefits, side-effects, availability and costs.
Certain anti-psychotic drugs are Amisulpride, Olanzapine, Risperidone and Clozapine. These drugs are effective but are associated with greater side-effects. Clozapine is an effective treatment for those who respond poorly to other drugs (“treatment-resistant” or “refractory” schizophrenia), but it has the potentially serious side effect of agranulocytosis (lowered white blood cell count).
CHLORPROMAZINE- Chlorpromazine was discovered in 1950 and was the first antipsychotic. It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system. Its introduction has been labeled as one of the great advances in the history of psychiatry. It is available as a generic medication. The wholesale cost in the developing world is between US$0.02 and US$0.12 per day. In the United States it costs about US$2 per day.[8]
LATEST RESEARCHES
1. On 8th June 2015, Esther Walton and others published a research paper citing the “ Correspondence of DNA Methylation between blood and brain tissue and its applications to Schizophrenia Research”. They have found some proxy areas of methylation and proclaiming to find epigenetic differences in schizophrenia.[9]
2. Dr. Yinghua Yu at University of Wollongong have found some promising results with Teasaponin@ supplementation.[10]
# Research has found a tentative benefit in using minocycline to treat schizophrenia. Nidotherapy or efforts to change the environment of people with schizophrenia to improve their ability to function, is also being studied; however, there is not enough evidence yet to make conclusions about its effectiveness.Negative symptoms have proven a challenge to treat, as they are generally not made better by medication. Various agents have been explored for possible benefits in this area. There have been trials on drugs with anti-inflammatory activity, based on the premise that inflammation might play a role in the pathology of schizophrenia.
TERMINOLOGY
# Catatonic behavior- It is a state of psychogenic motor immobility and behavioral abnormality manifested by stupor.
# Schneiderian first rank symptoms- These are the symptoms of schizophrenia that encompass a small range of hallucinations and delusions specifically; auditory hallucinations, thought broadcast, thought insertion, thought withdrawal, and delusional perception.
# NOTCH 4- Neurogenic locus notch homolog 4 also known as notch 4 is a protein that in humans is encoded by the NOTCH4 gene located on chromosome 6. Notch protein family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling pathway is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells.
# Zinc Finger protein 804A — Zinc finger protein 804A is a protein that in humans is encoded by the ZNF804A gene. The human gene maps to chromosome 2 q32.1. In humans, ZNF804A is expressed broadly throughout the brain, especially in the developing hippocampus and the cortex, as well as in the adult cerebellum. ZNF804A is expected to bind DNA and thus regulate gene expression like other zinc finger proteins. Interestingly, the mouse homologue of ZNF804A, zfp804a, has recently been reported as a target for HOXC8, suggesting that ZNF804A may be involved in the regulation of early development.
# Non celiac gluten sensitivity — It is defined as “a clinical entity induced by the ingestion of gluten leading to intestinal and/or extraintestinal symptoms that improve once the gluten-containing foodstuff is removed from the diet, and celiac disease and wheat allergy have been excluded”.[
# Anti gladin antibodies — Anti-gliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies. Some of these antibodies can detect proteins in specific grass taxa such as Triticeae.
SUMMARY
After so much of discoveries, even still the scenario of schizophrenia have not changed much. Frequently usage of anti-psychotic drugs have actually made patients more prone to other diseases.
In the treatment of Schizophrenia, the promising field is quite genetics especially evolutionary genetics which can be collaborated with molecular genetics to find some strong evidences in future.
REFERENCES
1. A typological model of schizophrenia based on age at onset, sex an familial morbidity. Acta Psych8atr. Scand, 89, 135–141(1994).
2. Dr. Robin Murray
3. NIMH
4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington: American Psychiatric Publishing. ISBN 978–0890425558.
5. Jakobsen KD, Frederiksen JN, Hansen T, et al. (2005). “Reliability of clinical ICD-10 schizophrenia diagnoses”. Nordic Journal of Psychiatry. 59 (3): 209–12. doi:10.1080/08039480510027698. PMID 16195122
6. en.wikipedia.org/wiki/Dopamine_hypothesis_of_schizophrenia
7. Konradi C; Heckers S (2003). “Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment”. Pharmacology and Therapeutics. 97 (2): 153–79. doi:10.1016/S0163–7258(02)00328–5. PMID 12559388.
8. “Chlorpromazine HCL”. International Drug Price Indicator Guide. Retrieved 1 December 2015.
9. doi.org/10.1093/schbul/sbv074
10. http://onlinelibrary.wiley.com/doi/10.1002/mnfr.201500205/full
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About:
Dr. Ravishankar Ramachandran is an internationally renowned structural biologist and drug-discovery scientist working on TB. He is also leading several efforts of academia-industry collaboration.
Dr. Sukant Khurana runs an academic research lab and several tech companies. He is also a known artist, author, and speaker. You can learn more about Sukant at
or
and if you wish to work on biomedical research, neuroscience, sustainable development, artificial intelligence or data science projects for public good, you can contact him at skgroup.iiserk@gmail.com or by reaching out to him on linkedin https://www.linkedin.com/in/sukant-khurana-755a2343/.
Here are two small documentaries on Sukant and a TEDx video on his citizen science effort.
