Background And Pathophysiology Of Schizophrenia Psychology Essay

Background And Pathophysiology Of Schizophrenia Psychology EssaySchizophrenia is a unspeakable chronic psychotic person disorder associated with the brain and is characterised by symptoms classified into trinity major categories domineering, veto and cognitive symptoms. Positive symptoms include h wholeucinations, delusions and thought disorder. proscribe symptoms consist of social withdrawal and flattening of emotional responses. In addition to this, deficits in cognitive function such as attention and memory argon withal often present in schizophrenic patients unitedly with dread and depression. (Rang, 2007) (Lewis J A Lieberman 2000)Studies energise shown some(prenominal) neurotransmitter systems such as serotonin, glutamate and dopamine to be involved in processes guide to the expression of the symptoms experienced in schizophrenic disorder. Among these, the dopamine conjecture has received the most attention and it get out be the focal point of this look for.Serot onin, an essential neurotransmitter, has its place in explaining schizophrenia by trying to explain the ele workforcets of the disorder which were initially unexplained. This consisted of the negative symptoms and the actions of antipsychotic agents. Its role was recognise in the 1950s when it was discover how similar serotonin was to LSD (lysergic stifling diethylamide). LSD ca wasting diseases psychotic symptoms as it competes with serotonin and occupies its sense organ sites. A usual antipsychotics as well as blocking dopamine sense organs, too act as 5-HT receptor oppositions. This guesswork was confirmed when typical antipsychotics were combined with a 5-HT2 ant champion such as ritanserin. This military issueed in relief of negative symptoms and extrapyramidal view install. (Sadock, 2000)Glutamate has also been implicated in schizophrenia. This hypothesis is derived from evidence using PCP, a glutamate NMDA receptor antagonist. Administ scabion produces psychotic sy mptoms and cognitive dysfunction in healthy subjects (Krystal et al. 1994) and negative cognitive symptoms in patients with schizophrenia. (Lahti et al. 1995) Phencyclidine, ketamine and dizocilpine, also glutamate NMDA receptor antagonists, provide psychotic symptoms in humans. Studies acquit also shown that in that location is reduction in glutamate receptor density and glutamate concentration in post-mortem brains of schizophrenic patients. (Rang 2007)The most common theory relating to schizophrenia is the dopamine atomic number 53. The first formulation of the dopamine hypothesis suggests that purposeless mesolimbic dopamine is the reason for the positive symptoms. The evidence that this idea was based on included amphetamine abuse which increased synaptic dopamine tip to delusions (Laruelle et al. 1996) and that all antipsychotic do mediciness block dopamine D2 receptors.As this theory implied trim dopamine is responsible for positive symptoms, what is responsible for th e negative and cognitive symptoms? Well, inquiry has shown that negative and cognitive symptoms ar the result of deficient dopamine in the pre fontal cortex due to D1 receptor dysfunction (K. L. Davis et al. 1991)There acquit been practicable definitions of schizophrenia unquestionable in an attempt the reliability of the diagnosis The internationalistic Classification of Diseases (ICD-10) and The American Psychiatric Associations Diagnostic and Statistical method (DSM-IV-TR) and two contain lists of criteria notwithstanding also insist that symptoms must bring forth persisted for 6 months.PICTURESchizophrenia normally presents itself in late adolescence or in early adult life (Kirkbride et al. 2006) with males having an earlier onset than females. In the UK, the typify age of first admission is about 22 years for men and 27 years for women. (Castle R M Murray 1991)Females also tend to fall in fewer negative symptoms and a better take than males.According to leading ex perts in this disorder, they have set that it is ca utilize my many work outs. One major factor is genetics, and schizophrenia draws in 10% of pack who have parents, brother or sister (first degree relatives) with the disorder. People who have grandparents, cousins or aunts and uncles (second degree relatives) also develop this disorder a lot more than the general public. (Kendler et al. 1993) approximately principal(prenominal)ly, the risk is at its greatest for a person who has a reduplicate with schizophrenia. (Irving Gottesman 1991)PICTURESeveral genes are related with the risk of schizophrenia but formerly it was believed thither is no particular gene that is responsible for the complaint itself. Studies have shown that people with schizophrenia also have many antiquated gene mutations which involve many genes and disrupt the growth of the brain.However in juvenile times, new seek has shown there may be several susceptible genes. One such gene is DISC1 which could be linked to the discipline and intercession of schizophrenia. DISC1 plays a key role in the growth of soul neurons. Mutated Disrupted in Schizophrenia (DISC1) gene is seen to disrupt the growth and development of cells in the brain. When DISC1 levels were reduced in mice, cells in the brain fai take to divide and the mice developed symptoms that mimicked schizophrenia in humans. (REFERENCE IMPORTANT ONE)Other than genes, environmental factors are in all likelihood outstanding in the development of schizophrenia. These include exposure to infections, immunocompromised, stress and macrocosm in contact with toxic chemicals during childhood may slightly manipulate brain development. (Marcel ET AL REFERENCE 1999)Chlorpromazine was the first drug discovered to have antipsychotic properties, followed by haloperidol which was widely prescribed. This is an example of typical first generation medical examination specialtys and produced D2 receptor blockade. By 1980, second generati on maverick drugs were out, most notably clozapine which was seen to be more potent in shell outing chronic patients. These had the do goods of also reducing negative symptoms and extreme side effectuate.pharmaceutic companies in the 1990s started to take advantage of clozapine and develop drugs without its side set up and olanzapine is another popular uncharacteristic drug.In 2005, there was a case through with(p) known as the CATIE study, in the USA, compare the metier of antipsychotic drugs in clinical settings. It was seen that there were high rates of discontinuation 64-82% over 18 months, due to patients not being able to bear side effectuate. Lack of efficacy was also found for all antipsychotic drugs in the study, although olanzapine was most effective (terms of discontinuation rates) than other drugs in the study. patronage this, olanzapine was associated with greater weight gain and increase glycosylated haemoglobin, cholesterol and triglycerides. These changes could have heartbreaking implications such as development of metabolic syndrome. (Jeffrey A. Lieberman et al. 2005)So why use or develop Chinese herb ex parcel of lands as a sanativeal tool for schizophrenia?Although antipsychotic medical specialty is salve the foundation for the preaching in schizophrenia, it still leaves some people with unbearable side effects and distressing symptoms.The most common side effects are Parkinsonism, dystonia and akathisia and are most common with haloperidol and fluphenazine. (Schillevoort et al. 2001) (Levinson et al. 1990) Dystonic spasms affect the neck muscles tongue and face, and occur within a few days of discussion and are obsess at high doses. Akathisia is the restless leg syndrome and is characterised by great urges to give notice and difficulty in sitting still. Anti-cholinergic drugs can relieve these symptoms they should not be effrontery routinely as they also cause side effects such as blurred vision, constipation, dry mout h and euphoria. It is also important to remember that not all patients will get side effects from taking antipsychotics. other long term side effect is tardive dyskinesia which is slow irregular movements particularly in the regions of the mouth, lips and protrusion of the tongue. Approximately 5% of the patients on antipsychotic medication developing this each year, but there is evidence that the incidence may be declining with increasing use of atypical antipsychotics. (Tarsy Baldessarini 2006)Due to the side effects, herbal tea medicines are comm solitary(prenominal) used for psychiatric purposes in both the developed and developing countries. (Walter Rey 1999) Studies have shown that some Chinese herbal medicines are effective for psychosis and that if used in conjunction with westbound medication, they enhance antipsychotic efficacy and reduce adverse effects. Another important aspect is that, Chinese herbs may be more accessible, acceptable and cheaper than drugs already available.Chinese herbal medication includes plants, fungi, resins, animal and mineral substances which are effrontery within a formula which typically consist of 4 to 12 herbs. Administration is in the form of decoctions, pills, powders, tablets, phials and as standardized plant extracts.Chinese herbal medication has been known to treat schizophrenia for over 2000 years although the methods used in Traditional Chinese medicine to diagnose and treat schizophrenia differs from that used in western medicine. In western medicine, it is usually diagnosed by criteria such as the Diagnostic and Statistical Manual (DSM) or the International Classification of Diseases (ICD) but in Traditional Chinese Medication, its diagnosed by the Chinese Classification of Mental Disorder (CCMD). icon shows the difference among diagnosing and treating Schizophrenia using conventional and Chinese herbal medicationTraditional Chinese medicine unalikeiates schizophrenia into syndromes which determine th e course of treatment. and so if two people are to be diagnosed with schizophrenia could have different clinical features (syndromes) therefore will require different medications. Each syndrome has a specific herbal formulation, but patients typically have mixed clinical features therefore they require precise formulations made by adding or subbing herbs. (Rathbone et al. 2007)Hype or hope? Is there really a benefit of using Chinese herbs as a therapeutic tool of schizophrenia?There have been several clinical trials done using Chinese herbal medication in the treatment of schizophrenia. One of the earlier studies was done using Dang gui cheng qi tang as the herbal medication given to the treatment concourse without the addition of the antipsychotic chlorpromazine which the command group received. The setting was in a hospital and participants were divided into groups randomly. It was account that no participants left the groups early and the result showed that the global state of matter outcome not improved /worse favoured the control group receiving chlorpromazine. (Rathbone et al. 2007) These results should be handle with caution given design limitations such as it being only conducted for 20 days, but nevertheless do not support that herbal medication should be used by itself for the treatment of schizophrenia.Further research and trials have been done which has incorporated using herbal medication together with an antipsychotic versus an antipsychotic alone. In 1997, Chinese herbal medications Dang gui cheng qi tang or xiao plus an antipsychotic was given to a treatment group compared to just the antipsychotic given to the control group. The allocation was randomized, lasted for 12 weeks and included hospital as well as community setting. The result showed that the treatment group come tod significantly lower for the outcome of global state not improved/worse than the control group. (Rathbone et al. 2007)Global data score from the Clinical Global I mpression graduated table (a rating scale meter severity of symptoms, treatment response and efficacy of treatment) also favoured treatment groups that took the herbal medication plus antipsychotic. ginkgo biloba was used with an antipsychotic for the treatment group in 1996 (Rathbone et al. 2007) and Shui zhi and Da huang were used with chlorpromazine. There were side effects associated with taking antipsychotics and taking herbal medications with antipsychotics showed that extra pyramidal side effects still arose. Constipation was however lower in the treatment group. (Rathbone et al. 2007)In 2001, Zhang et al did a study giving a treatment group Ginkgo biloba with haloperidol with the control group only receiving the latter. When compared, the study showed there was no difference between treatment group and control group when comparing negative symptoms and also when looking at Brief Psychiatric range Scale scores. However, the scale of positive symptoms did marginally favour the treatment group. (Rathbone et al. 2007)For all studies done in the past, we have to be aware that application of Chinese herbal medication is based on syndrome differentiation with failure of applying this differentiation resulting in ineffective or harmful treatment. There is no cover evidence that when given alone, Chinese herbal medications offer benefits which are contact or even greater than antipsychotic drugs. When the herbal drugs are used with antipsychotics, they may offer improvement in symptoms but as there is still limited evidence in regards to Chinese herbs and traditional Chinese medication, this approach must still be considered new and more probe is needed.Stepholidine is an active ingredient of the Chinese herb Stephania intermedia Lo, and belongs to an alkaloid group tetra-hydroberberine. (S. X. Xu et al. 1989)Initial research had shown that Stepholidine decreased stock pressure without exerting any adverse effects on the heart as well as exhibiting anal gesia and any sedating effects on the central nervous system.Recent studies have shown stepholidine to be a pioneering drug in the treatment of schizophrenia because it is a dopamine D1 receptor agonist and a D2 receptor antagonist. Due to the pathogenesis of this disease suggests the dysfunction of D1 receptors in the medial prefrontal cortex, which is accompanied by hyperactivity of D2 receptors in subcortical regions such as ventral tegmental theater (VTA) and the nucleus accumbens (NAc), when developing a antipsychotic drug should possess dual agonistic and antagonistic actions on the receptor. Stepholidine and its analogues tick these two important boxes.Stepholidine acts through D1 receptors to increase adenylyl cyclase activity and subsequent signalling pathways regulated by adenylyl cyclase might be responsible for the physiological responses, including rotational behaviour and changes in the firing activity of the neurons induced by Stepholidine.By contrast, Stepholidine i nhibits both D2 auto-receptor talk terms feedback inhibition of dopamine containing neurons and D2 receptor mediated effects on cigarette non dopamine containing neurons. (Guo-Zhang Jin et al. 2002)There are several symptoms related to schizophrenia and insomnia is one of the most common. This could be partly related to the over-activity of the dopaminergic system. There has been a study done to show whether stepholidine modulates sleep behaviours. This was done in mice and the sleep-wake profiles were observed. From this study it has been reason out that stepholidine significantly increased the amount of NREM sleep and prolonged the date of NREM sleep episodes, with reduction in the amount of wakefulness. Stepholidine had no effect on either the amount of REM sleep. Because it master(prenominal)tains NREM sleep in mice, it is suggested that it has the potential to be also used in the treatment of insomnia. (Qiu et al. 2009)Figure 1 shows the dual action of Stepholidine. Dopami ne (DA)-containing neurons in the ventral tegmental area (VTA) project to the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). The schizophrenia hypothesis suggests that D1 receptor dysfunction in the mPFC leads to the negative symptoms of schizophrenia and the D2 receptor hyperactivity in the sub-cortex nuclei leads to the positive symptoms of this disorder 1-4. The D1 receptor agonist effect of SPD in the mPFC is suggested to better the negative symptoms of schizophrenia, whereas the D2 receptor antagonist effect of SPD that predominates in the sub-cortex would improve the positive symptomsThe Stanley Medical Research Institute (SMRI) awarded a grant of Canadian $330,000 to Dr. Shitji Kapur and Dr. David Mamo in 2006 to study L-Stepholidine. The work they would do would be built up from previous knowledge of the drug already known. They conducted preclinical studies in rats and it showed to be a very promising compound. The goal then was to give it to humans and tone its D2 binding in an attempt at showing it indeed is a D2 drug in vivo using PET, and also estimate its expected therapeutic dose for futurity clinical studies. Having had several correspondences Dr Mamo, he has informed me that the main company in China had stopped the exertion of Stepholidine and for ensuring that the compound is thoroughgoing(a) without any contaminants and to assure the local regulatory authority the research was a safe study, they decided not to use stepholidine from China. Dr Kapur and Dr Mamo then collaborated with a apothecary to synthesize stepholidine in a lab. Synthesis was fine, but the problem was that they couldnt scale up the production to gram scale. A chemist had told him with further work, production was possible, but the SMRI was not willing to wait for this. The funding had to be given up but not for the reason that the drug wasnt showing promise.Another drawback in stepholidine is its bioavailability. Drugs given orally, acting on the centra l nervous system, should have good bioavailability and good blood brain barrier penetration. In rat based assays, it was seen that stepholidine, when administered orally, was poorly available to general circulation but could cross the blood brain barrier easily, resulting in good entry into the brain. Stepholidine was also found to have good permeability of the membrane that was not affected by efflux transporters such as P-gp or MRP2. Stepholidine which was absorbed from the gastrointestinal tract was also rapidly eliminated by glucuronidation of phenolic hydroxyl group, and less by sulphation, methylation, demethylation and /or N-oxidation. This poor bioavailability achieved by stepholidine could be due to the extensive pre systemic metabolism. A way to overcome this would be to develop pro-drugs, which would be chemically modified versions of stepholidine which will undergo enzymatic or chemical mutation for the active drug to be released. Example of this might be to deepen th e hydroxyl groups of stepholidine. (Sun et al. 2009)Due to its poor bioavailability, there has been significant development in recently towards the modification of stepholidine by development of series of derived functions. One derivative that has improved bioavailability while maintain the pharmacological properties of stepholidine, is bi-acetylated l-stepholidine.In recent times, although there has been an increase in material prosperity and growing success of traditional western medication, there has been an overall increase in psychotic disorders especially schizophrenia. Psychiatric patients not only want their symptoms to disappear, they also want to stretch to lead a normal life without all their troubles. Psychiatric patients have better resources for the treatment now than ever before, but due to buy at disappointments in western medication especially due to its side effects there has been increased growth of alternative and complementary methods in the treatment of pati ents. Sometimes patients also seek help from spell breakers, exorcists and herbalists.In recent times, according to the World Health Organisation (WHO) approximately 80% of people in the world have relied on herbs in satisfying their medical care needs, and developed countries such as Germany, Italy and even the USA have shown a dramatic increase in herbal medicine consumption.Stepholidine had led the way in recent drug discovery with it being both a D1 receptor agonist and D2 receptor antagonist activity. This is a unique(p) pharmacological characteristic of DH-THPBs (dihydro) and will be vital in the future when developing new antipsychotic drugs. More so, another DH-THPB, 12-chloroscoulerine has been found to have more potent dual action than stepholidine.In this project, I will analyse research done with stepholidine in regards to it being a therapeutic tool in the treatment of schizophrenia.Word count 2,992