Treatment of Schizophrenia - Case Study Example

Treatment of Schizophrenia by Modulating the Activity of Chemical Synapses Several disorders of the brain especially those related to psychiatrylike schizophrenia are a major challenge from the physician perspective. The etiology and pathogenesis of these disorders are not well understood and thus, institution of definitive treatment becomes difficult (Mirnics et al, 2001). While several studies have been conducted both on the central nervous system fluid of living human and forensic pathology on the dead human brain of the persons with disease, no concrete evidence has been found about the exact etiology of these disease (Moghaddam, 2003). Current treatment strategies are based on hypothetical models of etiopathogenesis and more research is warranted in this regard. Most of such treatment are based on alteration of the chemical synapses in the brain pathways. In this article, treatment of schizophrenia by modulation of the activity of various neurotransmitters will be discussed with reference to etiopathogenesis and hypothetical models of etiology. Schizophrenia which is commonly known as insanity or madness is one of the chronic psychotic disorders with affectation of perception, thinking and behaviour. It is the most severe end of a spectrum of schizophrenia related disorders. The process of this disease is actually not well understood. The disease can be mild or severe and stable or gradually deteriorating. Symptoms in schizophrenia can be positive or negative. Auditory hallucinations and delusions are characteristic symptoms of this disease (Gerstein, 2007). The most dangerous symptom is impaired information processing (Frankenburg, 2007). Symptoms in schizophrenia occur due to abnormalities in brain neurochemistry, neuroanatomy, and development (Gerstein, 2007). The prevalence of this condition worldwide is about 1% and it affects both sexes and all races and religions equally. In women, the onset of the disease is later and the severity of clinical symptoms is less when compared to men, probably due to anti-dopaminergic effects of oestrogen. Symptoms usually appear during adolescence and clinical deterioration occurs during the first 5- 10 years of disease onset (Gerstein, 2007). The anatomical abnormalities seen in schizophrenia are bilateral ventriculomegaly, decreased brain volume in certain regions like hippocampus and amygdala and abnormalities in neocortical and limbic regions and their interconnecting white matter tracts (Frankenburg, 2007). Overactivity of the dopamine system in the brain, especially those involving D2 receptors has also been demonstrated (Gerstein, 2007). Negative symptoms are caused due to hypodopaminergic activity in the mesocortical system and positive symptoms are caused due to hyperdopaminergic activity in the mesolimbic system. The fact that there is an increased incidence of this disease in the biological, but not adapted relatives of the patient and also that the condition is associated with left and mixed handedness points to genetic factor involvement in the causation of the disease. Infact, it has been estimated that the risk of schizophrenia in first- degree relatives is about 10%. In cases where both the parents are schizophrenic, the risk of development of the disease is as high as 40% in their child. Amongst dizygotic twics, the concordance for schizophrenia is about 10% and for monozygotic twins it is 40-50% (Frankenburg, 2007). Since maternal malnourishment and viral infections in pregnancy increase the risk of schizophrenia in the offspring, schizophrenia is probably a neurodevelopmental disorder (Frankenburg, 2007). The exact etiology is not yet deciphered; however, various social stressors can precipitate or exacerbate the symptoms. The molecular complexity and cellular perplexity of the central nervous system have created problems that are unique for the neuroscientist to design and implement various genomic studies that are functional. Microarray techologies are very powerful in the analysis of disorders of human brain. However, they are associated with some limitations. cDNA microarrays have been used to analyze the altered gene expression patterns between patients with schizophrenia and those without the disorder. This has revealed important aspects about the pathogenesis of the disease. One is the consistent decrease in the transcript groups that encode protein scheduled to regulate function of presynapse. the other is the changes gene which regulates signaling of G-protein. This new gene has never been associated with schizophrenia before. From these findings, it is evident that schizophrenia is mainly a disorder of synapse, thus leading to development of neurodevelopmental model. According to this model, impairment of the mechanics of the transmission of synapses in specific neural circuits during early years of life leads to altered formation of the synapse or pruning or even both, which ultimately contribute to clinical manifestation of the disorder (Mirnics et al, 2001). One of the theories for pathogenesis of schizophrenia has been imbalances of the neurotransmitter within the substance of the brain. Infact, the current pharmacological therapy for most psychotic disorders is based on these principles. Tricylic antidepressants and monoamine oxidase inhibitors have been developed for major depression based on these theories of brain disorders. It has been proposed that certain chemical imbalances in the brain cause clinical symptoms in MDD. These imbalances are said to occur in certain neurotransmitters like serotonin and noradrenaline. Even imbalances in dopamine have been noted in MDD (Bourin et al, 2002). Positron Emission (PET) studies have proved the relationship of altered glucose metabolism with respect to serotonin imbalances in MDD (Anderson et al, 2003). Infact, lower levels of glucose metabolism and cerebral blood flow in neocortical and subcortical regions in elderly patients with MDD has also been demonstated with PET (Kumar et al, 1993 and Sackeim et al, 1993). However, recent evidence has proved that it is the problem in information processing within neural networks, rather than changes in chemical balance that causes symptoms (Castren, 2005). Research into other mental illness like schizophrenia has demonstrated little information with reference to chemical disturbances in the brain. The first proposed theory for schizophrenia was monoamine hypothesis based on which selective serotonin reuptake inhibitors have been developed. However, this theory has been dismissed because of lack of association between the theory and clinical symptomatology. The next theory which came up was the dopamine hypothesis. This hypothesis was developed after researchers noted that phenothiazines, which block the function of the dopamine cause reduction in the symptoms of psychoses. This theory is further supported by the fact that amphetamines which increase the release of dopamine cause exacerbation of symptoms of psychoses in schizophrenia. Thus, according to the dopamine hypothesis of schizophrenia malfunctioning of the pathways of dopamine, especially the mesolimbic pathways causes positive symptoms of schizophrenia. Even this theory has been refuted by researchers because of some recent medicines given for schizophrenia decrease the positive symptoms even though they do not act much on the dopamine receptors. Current hypothesis for the pathogenesis of schizophrenia mainly arises from pharmacological observations made with reference to the drug phencyclidine. This drug was observed to produce psychotic symptoms like delusions and hallucinations similar to the positive symptoms of schizophrenia. Phencyclidine causes these symptoms by causing blockage of NMDA, which is a type of glutamate receptor. It actually selective binds to that receptor and hence is called NMDA agonist. Because of this, researchers have thought that pathological hypofunction of NMDA receptors is probably the cause for symptoms in untreated schizophrenia, like that produced on administration of phencyclidine. thi has led to the "NMDA Receptor Hypofunction Hypothesis of Schizophrenia". Descending glutaminergic pathway projects from the pyramidal neurons of the cortex to the dopamine neurons present in the ventral tegmental region. This pathway, normally, functions as a brake on the mesolimbic dopamine pathway. This is done by communication between various dopamine neurons in the ventral tegmental area through inhibitory ?-aminobutyric acid interneuron. This, ultimately leads to tonic inhibition of release of dopamine from the mesolimbic pathway. In untreated schizophrenia, there is hypoactivity of the NMDA receptors and thus the mesolimbic neurons cannot be effectively inhibited, resulting in hyperactivity of the mesolimbic dopamine pathway, because of which positive symptoms of schizophrenia occur (Stahl, 2007). Since phencyclidine administration causes symptoms similar to the affective, negative and also cognitive symptoms of schizophrenia, even these symptoms in schizophrenia can be attributed to the NMDA hypothesis. These symptom manifestation can be explained as follows. In normal persons, the descending cortico-brainstem glutamate neurons synapse directly onto and act as accelerators to the mesocortical dopamine neurons. Whenever there is hypoactivity of the NMDA receptors, there is loss of excitatory drive, resulting in hypoactivity and causing other symptoms of schizophrenia like affective, negative and cognitive symptoms. This hypothesis is supported by the fact that several genes that have been identified to be causing schizophrenia have an impact on the NMDA receptor. Genes that code for synaptogenesis, connectivity and neutotransmission at glutamate synapses level and also specifically for the NMDA receptors may cause dysregulation for the synapses, leading to hypofunction of the NMDA receptors and consequently symptomatology in schizophrenia (Stahl, 2007). The catechol-O-methyltransferase gene or the COMT gene that encodes for the intracellular enzyme COMT with is present in the post synaptic cleft is also found to be involved in the degradation and methylation of various catecholamine neurotransmitters like epinephrine, dopamine and nor epinephrine. Several allelic variant forms of this gene affects the activity of the enzyme. Another identified gene the RELN gene codes for reelin, a protein that plays a major role in the development of the brain and also GABAergic activity. In a Canadian study, another gene locus was identified, NOS1AP, that codes for nitric oxide synthase which is present in high quantities in the inhibitory neurons of the brain. Nitric oxide is an important intracellular messenger and any disequilibrium in it functions is expected to cause mental illness (Frankenburg, 2010). Thus pharmacotherapy for schizophrenia is based on these hypotheses of pathogenesis. The first line of treatment for schizophrenia is antipsychotic drugs like include clozapine, risperidone, haloperidol and fluphenazine decanoate. These drugs diminish positive symptoms and prevent relapses. Clozapine is an antagonist at cholinergic, histaminergic, adrenergic and serotonergic receptors. It is also a mild antogonist against D2. Risperidone is an antagonist for both dopamine-2 receptor and serotonin 5HT-2 antagonism. Fluphenazine blocks both postsynaptic dopaminergic D1 and D2 receptors in the brain. It depresses the reticular activating system to some extent and also has anticholinergic and alpha adrenergic effects. The drug of choice in acute psychosis is haloperidol which is dopamine-2 antagonist. Currently, many other drugs also have been used to treat schizophrenia. Aripiprazole is a partial agonist at dopamineD2 receptors and serotonin 5-HT1A receptors. It is also an antagonist at serotonin 5-HT2A receptors. It antagonizes alpha1 receptors. Quetiapine is also both dopamine and serotonin antagonist and is useful for long term management of the disease and is associated with less cholinergic side effects. Olanzapine is a selective and monoaminergic antagonist at Dopamine receptors 1-4, muscarinic receptors, serotonin receptors and alpha-1 and H-1 receptors. Paliperidone which is one of the active metabolites of risperidone is a central receptor antagonist of dopamine type-2 and serotonin type-2. Thus several pharmacological agents have been used to treat schizophrenia by altering the chemical synapses in the pathways in the brain, thus causing suppression of symptoms. However, they are associated with many side effects like include akathisia, dystonia, hyperprolactinemia, parkinsonism, tardive dyskinesia and neuroleptic malignant syndrome. Clozapine is associated with agranulocytosis. Anticholinergic agents are frequently used with antipsychotics to prevent dystonic or extrapyramidal symptoms. Other drugs which may be useful are antidepressants, mood stabilizers and anxiolytics (Frankenburg, 2010). References Bourin, M., David, D.J., Jolliet, P., Gardier, A. (2001). Mechanism of action of antidepressants and therapeutic perspectives. Therapies, 57(4), 385-96. Frankenburg, F.R. (2010). Schizophrenia. Emedicine from WebMD. Retrieved on 25th November, 2010 from http://emedicine.medscape.com/article/288259-overview Gerstein, P.S. (2007). Schizophrenia. Emedicine from WebMD. Retrieved on 25th November, 2010 from http://www.emedicine.com/emerg/TOPIC520.HTM> Kumar, A., Newberg, A., Alavi, A., Berlin, J., Smith, R., Reivich, M. (1993). Regional cerebral glucose metabolism in late-life depression and Alzheimer disease: a preliminary positron emission tomography study. Proc Natl Acad Sci USA , 90, 7019–7023. Moghaddam, B. (2003). Bringing Order to the Glutamate Chaos in Schizophrenia. Neuron, 40, 881–884. Mirnics, K., Middleton, F.A., Lewis, D.A., and Levitt, P. (2001). Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse. Trends in Neurosciences, 24(8), 479- 486. Sackeim, H.A., Prohovnik, I., Moeller, J.R., Mayeux, R., Stern, Y., Devanand, D.P. (1993). Regional cerebral blood flow in mood disorders, II: comparison of major depression and Alzheimer’s disease. J Nucl Med., 37, 1090–1101. Stahl, S.M. (2007). Beyond the Dopamine Hypothesis to the NMDA Glutamate Receptor Hypofunction Hypothesis of Schizophrenia. CNS Spectr., 12(4), 265-268 Read More