Researchers at Karolinska Institutet in Sweden and their colleagues in Germany, the USA and Finland have studied the safety of very long-term antipsychotic therapy for schizophrenia.
According to the study, which is published in the scientific journal World Psychiatry, mortality was higher during periods when patients were not on medication than when they were.
People with schizophrenia have an average life expectancy ten to twenty years below the norm, and there has long been concern that one of the causes is the long-term use of antipsychotic drugs.
Earlier compilations (meta-analyses) of results from randomised studies, however, indicated that the mortality rate for people with schizophrenia on antipsychotic medication was 30 to 50 per cent lower than those who have received placebo.
However, most of the studies done have been shorter than six months, which does not reflect the reality of treatment often being life-long.
Researchers from Karolinska Institutet and their international colleagues have now done a long-term follow-up, substantiating previous results and demonstrating that antipsychotic drugs are not associated with increased risk of co-morbid complications, such as cardiovascular disease. The study is the largest conducted in the field to date.
“It’s difficult to make comparisons between people on permanent medication and those who aren’t, as these groups differ in many ways,” says Heidi Taipale, assistant professor at the Department of Clinical Neuroscience at Karolinska Institutet.
“One common method of dealing with this has been to try to take account of such differences when making comparisons. However, we chose another method, in which each person was their own control, making it possible for us to make individual comparisons of hospitalisation during periods of antipsychotic medication and periods of no treatment.”
The researchers monitored just over 62,000 Finns who had received a schizophrenia diagnosis at some time between 1972 and 2014.
This they did by accessing various Finnish registries up until 2015, giving an average follow-up period of over 14 years. They found that the likelihood of being hospitalised for a somatic disease was just as high during the periods when the patients were on antipsychotic drugs as when they were not.
The differences in mortality, however, were noticeable. The cumulative mortality rate in the follow-up period at periods of medication and non-medication was 26 and 46 per cent respectively.
The researchers believe that there is overwhelming support for continual antipsychotic treatment for schizophrenia being a safer option than no medication.
At the same time, treatment brings the risk of adverse reactions, such as an increase in weight, which can raise the risk of cardiovascular disease.
The finding that treatment with antipsychotic drugs does not increase the likelihood of hospitalisation for cardiovascular disease may be attributable, argue the researchers, to the fact that the drugs can also have an antihypertensive effect and can reduce anxiety and the risk of substance abuse.
Antipsychotic treatment may also help patients adopt a healthier lifestyle and make them more likely to seek care when needed.
The researchers believe that there is overwhelming support for continual antipsychotic treatment for schizophrenia being a safer option than no medication.
“Antipsychotics get something of a bad press, which can make it difficult to reach out to the patient group with information on how important they are,” says Jari Tiihonen, professor of psychiatry at the Department of Clinical Neuroscience, Karolinska Institutet.
“We know from previous studies that only half of those who have been discharged from hospital after their first psychotic episode with a schizophrenia diagnosis take antipsychotic drugs.
Besides, there are many people with schizophrenia who are on long-term benzodiazepine medication, which is in breach of existing guidelines and is associated with increased mortality risk. Building trust and understanding towards the efficacy and safety of antipsychotic drugs is important, and we hope that this study can contribute to this end.”
Funding: The study was conducted with researchers from Finland, the USA and Germany and financed with grants from the Finnish Ministry of Social Affairs and Health via a development fund for Niuvanniemi Hospital. Heidi Taipele has received financial support from the Academy of Finland.
Schizophrenia (SCZ) is a severe psychiatric disorder that affects approximately 1% of the general population and is associated with a significant socioeconomic burden (Kahn et al., 2015).
Antipsychotics represent the mainstay treatment for SCZ, but around one-third of patients show no response (Gillespie et al., 2017). According to the American Psychiatric Association (APA) guidelines, treatment-resistant schizophrenia (TRS) patients are defined as those showing little or no response to at least two non-clozapine antipsychotic trials of adequate duration and dose range (Lehman et al., 2004).
Clozapine is the only treatment with an indication for TRS.
However, this drug is still underutilized due to monitoring requirement (Kelly et al., 2018) and potential adverse effects, some of which can be severe and life-threatening (Wheeler et al., 2009; Gillespie et al., 2017). Unfavorable response to first-line pharmacological treatments is generally associated with a more severe course of disease in TRS patients (Gillespie et al., 2017; Nucifora et al., 2018).
Moreover, TRS patients are highly exposed to the potential detrimental effect of inefficacious treatments, including risk for adverse reactions that could be obviated or reduced if treatment resistance was known in advance.
It has been suggested that differential treatment response to antipsychotics might underlie biologically distinct subphenotypes of SCZ (Farooq et al., 2013; Gillespie et al., 2017) and TRS might better constitute a distinct phenotype rather than just a more severe form of SCZ (Wimberley et al., 2017).
In this scenario, it has become clear that TRS patients would significantly benefit from the identification of clinical and biological markers to possibly predict the risk for treatment resistance before starting pharmacological treatments. However, TRS is poorly understood and its neurobiological underpinnings have yet to be clarified.
Data from family studies suggest that TRS is a heritable trait and that heritability might be stronger than in responsive SCZ (Nucifora et al., 2018). Candidate gene and genome-wide association studies (GWAS) have investigated how genetic variation might explain the interindividual variability observed in response to antipsychotics, but only a limited number of them focused on TRS (Nucifora et al., 2018).
The majority of these studies used clozapine prescription or treatment as a proxy for diagnosis of TRS, and the investigated genetic variants were selected mainly based on their previously association with SCZ. We can anticipate that findings from these studies have so far not allowed dissecting the genetic complexity underlining TRS.
Indeed, it has become clear that TRS is characterized by a complex polygenic nature. Most recent investigations have applied novel approaches such as polygenic risk score (PRS) and kernel support vector machine (SVM) to aggregate the effects of multiple variants contributing to disease risk.
These approaches might be better able to capture the polygenic architecture of psychiatric conditions as well as response to psychotropic medications. In light of these observations, in this article, we will review studies investigating the genetic bases of TRS with a focus on studies using polygenic analytical approaches.
The articles described in this narrative review were retrieved through a search on PubMed using the following keywords: treatment-resistant schizophrenia, antipsychotic response, genome-wide association study, machine learning, polygenic risk score, and support vector machine.
Overlap Between Predisposition to SCZ and Response to Antipsychotics
As in the case of other psychiatric disorders, pharmacogenetic studies of antipsychotics have explored the overlap between susceptibility to SCZ and probability to respond to pharmacological treatments. GWASs successfully identified a large number of underlying genetic loci involved in SCZ. Among the most significant efforts, a first mega-analysis of GWAS conducted by the Psychiatric Genomics Consortium (PGC), including 9,394 cases with SCZ and 12,462 controls of European origin, had identified seven genome-wide significant loci (Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium, 2011).
These results were replicated by a GWAS in which patients with SCZ treated with clozapine were compared with healthy controls (Hamshere et al., 2013). More recently, the second mega-analysis of GWAS conducted by the PGC (wave 2), including 36,989 cases and 113,075 controls, identified 108 loci associated with predisposition to SCZ (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014).
Besides single-nucleotide polymorphisms (SNPs), rare disruptive mutations identified with exome sequencing have also been shown to increase liability for SCZ (Purcell et al., 2014).
Based on the evidence that many of the variants identified by genome-wide studies on SCZ are located in genes playing a role in systems likely involved in its neurobiology, there is a rationale for investigating the association between genetic risk for SCZ and response to antipsychotics or TRS.
Ruderfer et al. (2016) evaluated both common and rare SCZ-associated loci for enrichment in drug targets, providing interesting evidence that supports the role of some of these genes as drug targets.
Authors used a gene-set analysis approach and found that 21% of 167 pharmacological subgroups were enriched for loci previously associated with SCZ.
Dopamine receptor D2 (DRD2) was among the loci contributing the most to this finding. Indeed, DRD2 encodes a known target not only of antipsychotics, but also of 46 different non-antipsychotic pharmacological subgroups out of the 167 evaluated in Ruderfer et al. (2016).
The gene set including targets of antipsychotics was enriched for common and rare variants previously associated with SCZ. Authors also compared TRS (532 SCZ patients treated with clozapine) with SCZ patients treated with other antipsychotics (n = 2,002), showing a higher number of disruptive mutations in genes targeted by antipsychotics in the TRS group.
Taken together, these results support the hypothesis that at least some of the genes identified as involved in the pathogenesis of SCZ might also explain part of the interindividual variability in response to antipsychotics as well as in susceptibility to TRS.
Source:
Karolinska Institute
Media Contacts:
Press Office – Karolinska Institute
Original Research: Open access
“20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20)”. Heidi Taipale, Antti Tanskanen, Juha Mehtälä, Pia Vattulainen, Christoph U. Correll and Jari Tiihonen, .
World Psychiatry doi:10.1002/wps.20699.
