The Link Between Neuroinflammation and Psychosis

Most of people think psychosis is splitting of the mind, is this true or not? If not, then what is psychosis, what are the causes of this disease, how it affects the human being? And what’s the role of neuroinflammation in psychosis?

Psychosis is a thought disturbance (psychiatric disorder) (Dr.Marian Gorge). Since long time ago, psychosis was generally described as significant impairment in the testing of the truth or “loss of boundaries of ego “witch interfere with the ability to meet ordinary demand”. Only 1-2% of the populations are susceptible to have disease.

In order to manifest psychosis, causes, diagnosis and symptoms should be included. The causes of psychosis may be genetic or due to brain changes like changes in the structure of the brain or in the brain chemicals; or due to hormonal effect like in postpartum psychosis. Psychosis can be divided according to the dominated symptoms into catatonic psychosis (purposeless movement and rigid immobility), disorganized psychosis, paranoid psychosis and undifferentiated psychosis.

Psychosis is a condition consisting of several symptoms. Psychosis is not an object which is nosological. It consists of many types of symptoms. Psychosis symptoms occur in a wide range of mental disorders and show a high degree of variation between people and a high degree of variation with the same person over time but the general meaning of psychosis is defined by the central clinical symptoms of delusions, hallucinations, and disorganized thought so, psychosis may include symptoms of mania and depression (Wolfgang Gaebel).

Psychosis has three groups of symptoms. The first is the positive symptoms which include Insomnia, Hallucination, catatonic behavior and paranoid delusion. And the second is the negative symptoms and include amotivation, apathy, asocial, and loss of pleasure in normally happy events. And the third group is the disorganized symptoms including the patient’s thoughts, talks, behavior and loss of concentration. The patient has to have at least two symptoms that last one month and at least one area if social or occupational function is significantly affected to be diagnose as psychotic patient.

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Pharmacotherapy of psychosis can be divided according to mechanism of actions into two types, typical and atypical. Typical antipsychotics act mainly as D2 blockers whereas atypical antipsychotics mechanism is to block both 5HT2A and D2. An atypical APD is described more precisely and simply as one that produces minimal EPS (Extrapyramidal side effects) at clinically effective doses (Meltzer HY., 2000), which is considered as one of the major side effects found in typical antipsychotics. For this reason, it is preferable to start the treatment with them according to the American psychiatric association. Some examples of atypical APD are clozapine (Schulte P., 2003), risperidone, quetiapine, olanzapine (Y. Meltzer., 2013), sertindole, sulpiride and aripiprazole. Clozapine is the gold standard due to its high efficacy in treating positive symptoms in patients with treatment-resistant schizophrenia (TRS) (Kane J, 1988). However, it has some side effects like agranulocytosis, seizures and the side effects of atypical APD generally include weight gain, effect of that of atropine, postural hypotension and sedations.

Pharmacotherapy by typical antipsychotics includes three generations which have the same efficacy but different potency so they generally cause the same effect but with different doses. Typical antipsychotics can be classified according to the potency to: high potency drugs (eg: Trifluperazine, Fluphenazine, Haloperidol and Zuclopenthixol) , moderate potency drugs (eg: Chlorpromazine and Loxapine) and low potency drugs (eg: Thoridazine). These drugs have many side effects which may be due to dopamine blocking like Extrapyramidal side effects (dystonia, Akathisia, Pseudo-parkinsonism, Tardive dyskinesia ), neuroleptic malignant syndrome and endocrine disturbances and may not like sedation and postural hypotension.

The original experiments undertaken to explain the brain pathology of psychosis date back to 1935 and included the study of brain structures of people with psychosis using X-ray imagery by using pneumoencephalography that was very painful. Studies have shown that neurotransmitters can play a role in depression in the brain (e.g. serotonin and dopamine). Some studies reveal that 5-HT2A receptor activation can lead to hallucination. Hallucination and delusion are not the biggest issues in psychosis, but the inability to differentiate between them and reality. In people who have auditory hallucinations, brain scans using PET (positron emission tomography) or fMRI (functional magnetic resonance) imaging indicate that areas of the brain that regulate speech and hearing are impaired (Dr. Ananya Mandal). Also motor disorders (MAs) are extremely prevalent both before any diagnosis and during treatment with antipsychotic medications in patients with first episode psychosis. However, it is not understood to what degree such phenomena have predictive value for long-term psychosocial functioning ( Cuesta MJ1…et al., 2019).

Naturally microglia cells are ramified but when inflamed, its structure changes to the amoeboid form. Microglial cells play a role in the removal of agents that cause infections, so stimulation of these cells leads to inflammation of the brain tissues. When brain tissues are injured or inflamed, an out of control activation of microglia occurs which lead to many CNS diseases as Alzheimer and psychosis. Some research reported an increased in the density of microglia cells in schizophrenia, but other research were unable to provide that (Janine Doorduin…et al.,2009).

When microglia cells are activated, an increase in the peripheral benzodiazepine receptors (PBRs) which are present in the outer membrane of the mitochondria and are antagonist to 11C-(R)-PK11195 occurs. So, in a study applied on patients having psychosis, 11C-(R)-PK11195 is given to them and it’s found that, the number of 11C-(R)-PK11195 bound increased which confirms that there is a great relationship between psychosis and neuroinflammation but still not necessary. The neuroinflammation which was contained in the Hippocampus may reflect the outstanding vulnerability of this area experiences psychosis. In addition to increasing the number of microglia cells in psychotic patients due to neuroinflammation, neuroinflammation can also causes a stimulation of astrocytes.

The genetic studies also give an indicator of the importance of inflammation in schizophrenia. Multiple genome-wide association studies have concluded that the main island of MHC on chromosome 6, which is a pillar of the immune system, has the greatest allegiance to schizophrenia. In particular, it was found that the complement component 4 (C4 gene) within the island of human leukocyte antigen (HLA) has a strong association with schizophrenia (Purcell SM, 2009). C4 includes both the opsonization of pathogens and synaptic pruning, which can be related to the developmentally timed existence of the risk of schizophrenia.

References

1. Lecture 7 , Dr. Marian gorge.
2. American Psychiatric Association Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders, 4th edition text revision (DSM-IV-TR). Washington, DC: American Psychiatric Association, 2000.
3. Focus on psychosis , Wolfgang Gaebel,. Jürgen Zielasek, , Dialogues Clin Neurosci. 2015 Mar; 17(1): 9–18. (4) An atypical compound by any other name is still a….. . Meltzer HY. 2000. Psychopharmacology (Berlin) 148(1): 16-19 (5) What is an adequate trial with clozapine? Therapeutic drug monitoring and time to response in treatment-refractory schizophrenia Schulte P. 2003.. Clin. Pharmacokinet. 42(7): 607–18 (6) Update on typical and atypical antipsychotics. Y . Meltzer. Vol. 65:393-406 (volume publication date: Janury 2013) . https://doi.org/10.1146/annurev-med-050911-161504.
4. Clozapine for the treatment-resistant schizophrenia. A double-blind comparison with chlorpromazine. Kane J, Honigfeld G, Singer J, et al. 1988. Arch. Gen. Psychiatry 45(9): 789–96.
5. Psychosis Pathophysiology. Dr. Ananya Mandal.
6. Motor abnormalities in first-episode psychosis patients and long-term psychosocial functioning. Cuesta MJ1, García de Jalón E2, Campos MS3, Moreno-Izco L4, Lorente-Omeñaca R4, Sánchez-Torres AM4, Peralta V2. 201 . 2018 Oct;200:97-103.doi: 10.1016/j.schres.2017.08.050. Epub 2017 (10) Neuroinflammation in Schizophrenia-Related Psychosis: A PET Study. Janine Doorduin. Erik F J de Vries. Antoon T Willemsen. Jan Cees de Groot. Page: 1801-1807. in Journal of Nuclear Medicine 50(11):1801-7 • November 2009. DOI: 10.2967/jnumed.109.066647 •
7. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.International, Schizophrenia Consortium., Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF, Sklar P. Nature. 2009 Aug 6; 460(7256):748-52.