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= Treatment resistant schizophrenia =

Overview
Treatment resistant schizophrenia (TRS) is the persistence of symptoms of the disease despite being treated with appropriate antipsychotics, and accounts for between 20% to 30% of all Schizophrenia diagnoses. People with TRS usually have a worse quality of life, as symptoms without relief can have a devastating affect on one's wellbeing. Schizophrenia is deemed treatment resistant after the attempt to relieve symptoms, using at least two antipsychotics, is unsuccesful. The more detailed definition of TRS has been discussed in great detail in the past with more recent developments being more inclusive of global functioning. Research has identified many aspects that vary in TRS such as the persons daily functioning skills, brain structure, functionality and chemistry.

Definitions
TRS has been defined as persistent schizophrenia symptoms that are non-responsive to two or more antipsychotic medications from both classes (first generation and second generation). Further to this, at least two of the critical psychosis symptoms (conceptual disorganisation, suspiciousness, hallucinatory behaviour and unusual thought content) must be present with severity of moderate to severe, as well as the full extent of symptoms being experienced throughout, despite treatment being administered and adhered to.

It is now recognised that it is important for definitions of TRS to take into consideration the level of disruption in daily functioning, as well as assessing the reduction of clinical symptoms. Deciding on a clear definition of TRS has been a topic of discussion for many years as in the past it has focused solely on clinical measures of symptoms using rating scales of psychopathology, but by using more global measures that incorporate factors such as cognition, daily functioning, re-hospitalisations, psychosocial abilities.

It is also important to outline the key aspects that define TRS in order to know what can be a measure of successful or unsuccessful treatment. As with definitions of the disease, the definitions of response have relied on measuring the effects of antipsychotics on scales such as the Positive and Negative Syndrome Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS). However other factors are now being included in response definitions, in line with definitions of TRS, that are a more global approach. This encapsulates more real-life measures of how patients respond to treatment.

It is important that treatment resistance is clearly distinguished from non-adherence. Where symptoms still occur due to the person not taking their medication regularly and consistently, it is defined as non-adherence, whereas treatment resistance is having the full extent and persistent symptoms despite taking medication according to the treatment plan. These can sometimes be confused as non-adherence can be common in the schizophrenia population.

What makes TRS different
It has been a topic of discussion whether TRS is distinctly different from treatment responsive Schizophrenia. It was concluded from a systematic review that there is a trend towards a distinction between the two, with TRS being characterised by reduced grey matter, abnormal glutamate activity and lack of abnormal dopamine activity as is usually found in treatment responsive schizophrenia. However, it is recognised that more research needs to be done on these distinctions in order to be able to identify TRS earlier, enabling earlier intervention, and to design appropriate treatment plans to this potential subset of patients. In order to do this, studies need to have more robust methodologies that can replicate findings as there are many with problems of sample size, definitions of TRS and using cross-sectional designs.

Everyday functioning
People suffering with TRS have approximately 20% lower quality of life scores than those with treatment responsive schizophrenia in remission. They were also more likely to smoke (56%), take part in alcohol abuse (51%) and drug abuse (51%), and have suicidal thoughts (44%). All of these involve a person's day to day life and shows how much TRS can affect their everyday functioning. Furthermore, patients who do not respond to treatment can cost any where from 3 to 11 times more than patients with treatment responsive schizophrenia.

Brain structure in TRS
Brain's of TRS patients have been found to have reduced volume when compared to people with responding schizophrenia. This was seen globally, as well as in more specific regions, such as the inferior and superior temporal gyri, the middle frontal gyrus, lateral occipital cortex and the cerebellum. It was also found that TRS patients had significant differences in grey and white matter in their brain when compared to healthy controls. They had increased amounts of white matter in the frontal, occipital and parietal regions, as well as reduced grey matter in the frontal and occipital regions. This finding reached significance in the comparison between TRS patients and healthy controls, however a significant difference was not found between treatment responsive patients and the control group. This shows these impacts on the brain are more severe in TRS patients than non-TRS patients.

It is still unknown whether these differences contribute to the treatment resistance of schizophrenia or whether they are a consequence of not having effective treatment leading to the effects of the disease continuing to damage the brain. But research such as this highlights that there are underlying biological disparities that either need to be stopped in their tracks earlier to prevent further damage, or that there are additional factors similar to these that play a role in treatment resistance.

Further research has shown a relationship between the response to the typical antipsychotic to treat TRS, Clozapine, and a person’s structure and metabolism in specific brain areas. It was found that grey matter in the dorsolateral pre-frontal cortex (DLPFC) and temporal regions were the areas of the brain most related to treatment outcome. This suggests that person’s brain structure in these areas could partially explain the unresponsiveness to treatment, but more research to replicate these results needs to be done.

Brain functionality in TRS
Differences in how the brains of those with TRS function when compared with healthy controls have been demonstrated through research. McNabb (2018) found these differences more specifically in ultra-treatment resistant schizophrenia (UTRS) patients and healthy controls. In this study it was found that functional networks did not work to the same level in UTRS patients when communicating between the parietal and cerebellar regions to the frontal region of the brain. This corresponds to another study that showed that the fronto-temporal, fronto-occipital and temporo-occipital networks displayed the most prevalent differences. The same study told us that TRS brains have a reduced resting state functional connectivity as a whole, with 3.4% of the functional networks being weaker than they are in healthy controls. However, local networks within the TRS brain were actually found to have increased functional efficiency, telling us that brains in those with TRS are better within specific areas of the brain but cannot then use this to communicate to other networks across the brain.

Neurotransmission in TRS
A systematic review found many studies had shown that abnormalities within neurotransmitter systems in the brain of TRS patients can exist, and could be possible markers or characteristics of the disease. They presented evidence that showed low levels of striatal dopamine synthesis in TRS, and in contrast higher baseline levels of synaptic dopamine was linked to predicting good treatment response.

It has also been found that those with TRS may have abnormalities in serotonin related genes, such as excitatory receptor genes, and those encoding for enzymes responsible for the process of developing serotonin. Additionally, higher levels of glutamate in the anterior cingulate cortex (ACC) have been reported in TRS compared to healthy controls. However, the majority of these findings have not been successfully replicated and so need further investigation.

Treatment options
The recommended treatment for TRS is the antipsychotic clozapine, after the failure to treat using at least two other antipsychotics. Clozapine is the medication that TRS patients have been found to be most responsive to. It was shown to be most effective in treating general psychopathology in many research studies when compared to other antipsychotic drugs. It has also been found in another review that many randomised controlled trials found clozapine to be successful in reducing symptoms such as suicidality, aggressiveness and number of admissions to hospital in TRS patients.

Other therapies that have been suggested as options to run alongside Clozapine to enhance positive effects are other anti-psychotic medication, repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS) and electro-convulsive therapy (ECT). However, it is also stated that as there may be evidence to support this, for some it may be weak (additional antipsychotic drugs), for others it is still only in the very early stages (rTMS and tDCS) and could also not know underlying mechanisms as well as long term effects or side effects, and should be used with caution (ECT).

Another review into the treatment of TRS looking at neuroimaging studies, tells us that the efficacy of clozapine is questionable as many of the results are confusing and biological underpinnings of the disease are unclear. They also stated that many of the studies focused on comparing TRS patients with healthy controls and not including responsive patients as a comparison option. Again this suggests that more research needs to be done on TRS, its treatment and its foundations to further understand TRS and whether it is a case of severity of the same disease as responsive schizophrenia or whether it is categorically different. It is still unclear from research whether these differences that have been observed are present before treatment is administered and can therefore provide insight into treatment resistance in the early stages of schizophrenia, or whether these changes occur as a consequence of progression of the disease after treatment resistance.