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    The present symposium at the 29th Annual EPA Congress in 2021 discussed the most recent research on polypharmacy approaches in the treatment of schizophrenia. Experts from across the globe outlined the conceptual basis for a rational, safe and evidence-based polypharmacy approach for schizophrenia, with talks from Professors Christian Schmidt-Kraepelin, Oliver Freudenreich, Mathias Zink and Alex Hofer. The symposium was moderated by Schmidt-Kraepelin and Freudenreich. Polypharmacy, defined as a treatment approach where two or more medications are prescribed to a patient is becoming more common in standard clinical practice for patients with schizophrenia. The rationale behind such approach is to improve treatment response and/or reduce the burden of side effects. Although not recommended in guidelines, in this symposium a way forward in developing a rational and evidence-based polypharmacy treatment plan was aimed. 

    Combination treatment: a risky business

    The symposium began with a talk by Professor Christian Schmidt-Kraepelin, Professor in the Department of Psychiatry and Psychotherapy at Heinrich-Heine-University, Germany. The focus of his lecture was the potential effects of using combination therapy with second generation antipsychotics other than clozapine.
    Professor Schmidt-Kraepelin started by discussing the available evidence regarding the efficacy and safety of combination treatments or so-called polypharmacy. Combination treatment is when two or more antipsychotics are utilized in order to enhance the therapeutic effects or mitigate side effects of certain drugs.1 According to the results of a Cochrane systematic review of 62 randomised clinical trials, combination treatment was able to reduce the risk of patients not responding to treatment by a risk ratio of 0.73.However, as Professor Schmidt-Kraepelin identified, the studies were quite different in their design and the quality was described as low.1 He also noted that combination treatment has the potential to be harmful since certain drug combinations carry higher risks of side effects, as well as the possibility of higher treatment costs.1
    Professor Schmidt-Kraepelin then went on to describe a trial carried out in Germany concerning the efficacy of combined therapy. The unpublished results of this 16-week trial called COMBINE (Comparison of Antipsychotic Combination Treatment of Olanzapine and Amisulpride to Monotherapy) assessed symptoms using the Positive and Negative Syndrome Scale (PANSS) in patients randomised to either combined therapy or monotherapy. The results showed that patients on combined therapy had a significant change in their PANSS total score and, interestingly, these changes were primarily due to changes in negative symptoms. Unfortunately, as Professor Schmidt-Kraepelin pointed out, combination therapy was associated with side effects including sexual dysfunction and weight gain. 
    The talk was concluded by summarising the use of combination therapy in treating schizophrenia. Professor Schmidt-Kraepelin recognised that while there may be some potential for effective treatment when used rationally, it should be used sparingly and only after monotherapy options have been exhausted, due to the risk of increased side effects. 

    Treating the untreatable: improving outcomes for treatment-refractory patients

    In the second talk of the symposium, Professor Oliver Freudenreich, Associate Professor of Psychiatry at Massachusetts General Hospital, introduced the strategies which can help in improving outcomes in treatment-refractory clozapine patients. 
    Before diving in, Professor Freudenreich defined treatment-resistant schizophrenia (TRS) as the presence of symptoms for at least 12 weeks, despite adequate treatment being attempted for at least two 6-week trials with 80% adherence.Unfortunately, TRS occurs in approximately 30% of schizophrenia patients, and for these patients according to several guidelines clozapine is recommended.2,3 However, in Professor Freudenreich’s clinical experience, the overall efficacy of clozapine is limited, and around half of his patients do not respond. Moreover, clozapine may have minimal effects on the positive and negative symptoms which make the disease so difficult to live with, and the medical disease burden remains high.3
    Professor Freudenreich went on to discuss the potential of augmentation strategies, methods which aim to improve treatment response to drugs like clozapine. While there is significant interest for this in clinical practice, the strategies to do so are limited. Interestingly, non-pharmacologic strategies have been identified as having potential, including cognitive behavioural therapy for psychosis (CBTp), hallucination focused integrative therapy (HIT) and repetitive transcranial magnetic stimulation (rTMS).2 
    It remains clear that more research needs to be carried out into TRS, and Professor Freudenreich emphasised that novel treatment strategies are needed. A new oral compound, SEP-363856, has been recently studied which acts on a different receptor type to typical antipsychotics.This non-dopaminergic drug was found to be able to reduce the PANSS score compared to placebo, but longer and larger trials are needed to properly understand the efficacy and potential side effects of this new drug.4
    Professor Freudenreich concluded his talk by pointing out that contributors to TRS are heterogeneous and multidimensional, and clinicians must take this into account.2 There may also be other contributing factors, such as access and continuity of comprehensive care, which could be targeted with non-pharmacologic interventions.Therefore, to properly treat TRS, all of these aspects should be considered in the overall care pathway to provide the best possible outcomes.  

    Antidepressants and antipsychotics: a useful pairing

    Professor Mathias Zink from the Central Institute of Mental Health at the University of Heidelberg, held the third talk on antidepressant therapy as an adjunctive treatment in schizophrenia management. He emphasized that this is an important area of research because depression is the most common comorbid psychiatric disorder in schizophrenia and is present in roughly 50% of patients.5 Because depression reduces life expectancy due to increased risk of suicide,6 being able to evaluate it objectively is essential. The use of tools such as the PANSS has some utility, but the Calgary Depression Scale for schizophrenia may be a more robust and useful measure. 
    In the beginning of the talk, Professor Zink brought up the effectiveness of cognitive behavioural therapy (CBT) in the treatment of depression.According to the UK NICE guidelines, CBT should be offered to all people with schizophrenia to mitigate the risk of depression.8 He also introduced pharmacological interventions which can optimise antipsychotic treatment, including the use of mood stabilisers and antidepressants.9 Antidepressants may have benefits in improving negative symptoms and quality of life in schizophrenia patients, Professor Zink highlighted. 
    However, care should be taken in this area of research since certain antidepressants like buproprion, have been linked with an increased risk of psychosis.10 Despite this, other research has suggested that the risk is related to the formulation of the drug, and extended-release formulations might be safer, especially when combined with antipsychotics.10 Other new antidepressants, such as the multimodal vortioexetine, have been studied in schizophrenia.11 Professor Zink demonstrated the potential of adjunctive vortioexetine in 20 schizophrenia patients, showing significant improvements in the PANSS score and Calgary Depression Scale.11
    To summarise, the use of antidepressant therapy in combination with antipsychotics can address several important aspects of schizophrenia. As well as this, robust evidence supporting non-pharmacological interventions like CBT points to other avenues to be explored. Overall, as Professor Zink concluded, antidepressants are well tolerated and well researched, and the benefits in schizophrenia seen so far hold promise for the future.

    Weighing up the risks: combination approaches in schizophrenia

    In the final talk of the session, Professor Alex Hofer, Associate Professor of Psychiatry, Psychotherapy and Psychosomatics at the Medical University Innsbruck discussed combination approaches to reduce weight-gain induced by antipsychotics. 
    Professor Hofer began by introducing obesity, which is becoming an increasing health problem worldwide, and in patients with schizophrenia the prevalence is as high as around 45-60%.12 Unfortunately, metabolic changes like weight gain are common in people with mental illnesses due to genetic and lifestyle factors.13 On top of this, psychotropic medications are known to increase the risk of weight gain, possibly due to hormonal changes, development of insulin resistance and changes to glucose regulation.13 Among the common antipsychotics prescribed, olanzapine and clozapine present with the highest risk, and aripiprazole and ziprasidone with the lowest.14
    Fortunately, switching from a high-risk antipsychotic to a lower-risk one can help to reduce weight and improve cardiometabolic outcomes.15 When deciding to switch drugs, the weight gain potential of both options should be considered, Professor Hofer emphasised. Furthermore, switching medication in stable patients should involve a consideration of the risks of psychiatric worsening.16 
    Professor Hofer continued by discussing other pharmacological strategies to control weight gain, including adjunctive aripiprazole and metformin as possibilities.16 In people taking antipsychotic medication, short-term trials have shown that metformin can reduce weight compared to placebo and may be used in both early and chronic patients.16,17 Furthermore, metformin plus lifestyle interventions have been shown to be even more effective than metformin alone.17 Non-pharmacological interventions, such as exercise and dietary changes
     can also be implemented alongside any treatment strategy to manage weight gain.
    As the talk came to a close, Professor Hofer emphasised the importance of considering weight gain as a significant side-effect of antipsychotics, as it is a frequent and often neglected clinical condition. While pharmacological interventions are an important part of the overall treatment plan, many different interventions exist and may be considered to control weight gain in patients with schizophrenia.


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    13. Siskind D, Gallagher E, Winckel K, Hollingworth S, Kisely S, Firth J, Correll CU, Marteene W. Does Switching Antipsychotics Ameliorate Weight Gain in Patients With Severe Mental Illness? A Systematic Review and Meta-analysis. Schizophr Bull. 6:sbaa191. doi: 10.1093/schbul/sbaa191. Epub ahead of print (2021)
    14. Cooper SJ, Reynolds GP, Barnes T, et al. BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. Journal of Psychopharmacology. 30(8):717-748 (2016)
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