Schizophrenia is a severe chronic psychotic disorder associated with the brain and is characterised by symptoms classified into three major categories; positive, negative and cognitive symptoms. Positive symptoms include hallucinations, delusions and thought disorder. Negative symptoms consist of social withdrawal and flattening of emotional responses. In addition to this, deficits in cognitive function such as attention and memory are also often present in schizophrenic patients together with anxiety and depression. (Rang, 2007); (Lewis & J A Lieberman 2000)
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Studies have shown several neurotransmitter systems such as serotonin, glutamate and dopamine to be involved in processes leading to the expression of the symptoms experienced in schizophrenia. Among these, the dopamine theory has received the most attention and it will be the focal point of this research.
Serotonin, an essential neurotransmitter, has its place in explaining schizophrenia by trying to explain the elements of the disorder which were initially unexplained. This consisted of the negative symptoms and the actions of antipsychotics. Its role was recognised in the 1950’s when it was discovered how similar serotonin was to LSD (lysergic acid diethylamide). LSD causes psychotic symptoms as it competes with serotonin and occupies its receptor sites. Atypical antipsychotics as well as blocking dopamine receptors, also act as 5-HT receptor antagonists. This hypothesis was confirmed when typical antipsychotics were combined with a 5-HT2 antagonist such as ritanserin. This resulted in relief of negative symptoms and extrapyramidal side effects. (Sadock, 2000)
Glutamate has also been implicated in schizophrenia. This hypothesis is derived from evidence using PCP, a glutamate NMDA receptor antagonist. Administration produces psychotic symptoms 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 have also shown that there 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 one. The first formulation of the dopamine hypothesis suggests that excess mesolimbic dopamine is the reason for the positive symptoms. The evidence that this idea was based on included amphetamine abuse which increased synaptic dopamine leading to delusions (Laruelle et al. 1996) and that all antipsychotic drugs block dopamine D2 receptors.
As this theory implied excess dopamine is responsible for positive symptoms, what is responsible for the negative and cognitive symptoms? Well, research has shown that negative and cognitive symptoms are the result of deficient dopamine in the pre fontal cortex due to D1 receptor dysfunction (K. L. Davis et al. 1991)
There have been operational definitions of schizophrenia developed in an attempt the reliability of the diagnosis; The International Classification of Diseases (ICD-10) and The American Psychiatric Association’s Diagnostic and Statistical method (DSM-IV-TR) and both contain lists of criteria but also insist that symptoms must have persisted for 6 months.
Schizophrenia usually 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 mean age of first admission is about 22 years for men and 27 years for women. (Castle & R M Murray 1991)Females also tend to have fewer negative symptoms and a better outcome than males.
According to leading experts in this disorder, they have found that it is caused my many factors. One major factor is genetics, and schizophrenia occurs in 10% of people 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) Most importantly, the risk is at its greatest for a person who has a twin with schizophrenia. (Irving Gottesman 1991)
Several genes are related with the risk of schizophrenia but previously it was believed there is no particular gene that is responsible for the disease itself. Studies have shown that people with schizophrenia also have many rare gene mutations which involve many genes and disrupt the development of the brain.
However in recent times, new research has shown there may be several susceptible genes. One such gene is DISC1 which could be linked to the development and treatment of schizophrenia. DISC1 plays a key role in the growth of individual 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 failed to divide and the mice developed symptoms that mimicked schizophrenia in humans. (REFERENCE IMPORTANT ONE)
Other than genes, environmental factors are probably important in the development of schizophrenia. These include exposure to infections, immunocompromised, stress and being in contact with toxic chemicals during childhood may slightly alter 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 medications and produced D2 receptor blockade. By 1980, second generation ‘atypical’ drugs were out, most notably clozapine which was seen to be more potent in treating chronic patients. These had the benefits of also reducing negative symptoms and extreme side effects.
Pharmaceutical companies in the 1990s started to take advantage of clozapine and develop drugs without its side effects and olanzapine is another popular atypical drug.
In 2005, there was a study done known as the CATIE study, in the USA, comparing the effectiveness 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 tolerate side effects. 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. Despite this, olanzapine was associated with greater weight gain and increase glycosylated haemoglobin, cholesterol and triglycerides. These changes could have serious implications such as development of metabolic syndrome. (Jeffrey A. Lieberman et al. 2005)
So why use or develop Chinese herb extracts as a therapeutic tool for schizophrenia?
Although antipsychotic medication is still the foundation for the treatment 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 treatment and are frequent at high doses. Akathisia is the restless leg syndrome and is characterised by great urges to move and difficulty in sitting still. Anti-cholinergic drugs can relieve these symptoms; they should not be given routinely as they also cause side effects such as blurred vision, constipation, dry mouth and euphoria. It is also important to remember that not all patients will get side effects from taking antipsychotics. Another 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 medicines are commonly 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 western 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 given 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, it’s diagnosed by the Chinese Classification of Mental Disorder (CCMD).
Figure shows the difference between diagnosing and treating Schizophrenia using traditional and Chinese herbal medication
Traditional Chinese medicine differentiates schizophrenia into syndromes which determine the course of treatment. Therefore 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 substituting 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 group without the addition of the antipsychotic chlorpromazine which the control group received. The setting was in a hospital and participants were divided into groups randomly. It was reported that no participants left the groups early and the result showed that the global state outcome ‘not improved /worse’ favoured the control group receiving chlorpromazine. (Rathbone et al. 2007) These results should be treated 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.
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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 scored 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 Impression scale (a rating scale measuring 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 Rating 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 concrete evidence that when given alone, Chinese herbal medications offer benefits which are equal 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 investigation 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 blood pressure without exerting any adverse effects on the heart as well as exhibiting analgesia 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 area (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 inhibits both D2 auto-receptor mediated feedback inhibition of dopamine containing neurons and D2 receptor mediated effects on target 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 concluded that stepholidine significantly increased the amount of NREM sleep and prolonged the duration of NREM sleep episodes, with reduction in the amount of wakefulness. Stepholidine had no effect on either the amount of REM sleep. Because it maintains 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. Dopamine (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 ameliorate the negative symptoms of schizophrenia, whereas the D2 receptor antagonist effect of SPD that predominates in the sub-cortex would improve the positive symptoms
The 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 measure 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 future clinical studies. Having had several correspondences Dr Mamo, he has informed me that the main company in China had stopped the production of Stepholidine and for ensuring that the compound is pure 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 chemist to synthesize stepholidine in a lab. Synthesis was fine, but the problem was that they couldn’t 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 wasn’t showing promise.
Another drawback in stepholidine is its bioavailability. Drugs given orally, acting on the central 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 systemic 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 transformation for the active drug to be released. Example of this might be to modify the 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 derivatives. 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 continue to lead a normal life without all their troubles. Psychiatric patients have better resources for the treatment now than ever before, but due to frequent disappointments in western medication especially due to its side effects; there has been increased growth of alternative and complementary methods in the treatment of patients. 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 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.
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