Schizophrenia treatment preferences of psychiatrists versus guidelines: A European perspective | European Psychiatry
Pharmacotherapy
Case A: First episode of schizophrenia
With more than 90% of participants recommending antipsychotics and choosing one of the three second-generation antipsychotics, results indicate high consistency in preferences for antipsychotics during the acute phase of schizophrenia. While guidelines, in general, do not prefer one antipsychotic over another but suggest consideration of various factors when choosing antipsychotics for first-episode psychosis, these results are partially comparable with the data from Eastern [Reference Szkultecka-Dębek, Miernik, Stelmachowski, Jakovljević, Jukić and Aadamsoo40] and Northern Europe [Reference Hamina, Taipale, Lieslehto, Lähteenvuo, Tanskanen and Mittendorfer-Rutz41, Reference Taipale, Puranen, Mittendorfer-Rutz, Tiihonen, Tanskanen and Cervenka42], where olanzapine was the most commonly prescribed, followed by clozapine and risperidone, but also with the data from the United Kingdom and the United States, where aripiprazole and quetiapine were the most prescribed drugs (including for bipolar disorders) [Reference Richards-Belle, Launders, Hardoon, KKC, Bramon and DPJ43, 44]. The majority would consider using more than one antipsychotic, which is not in line with any of the guidelines [Reference Højlund, Köhler-Forsberg, Gregersen, Rohde, Mellentin and Anhøj45].
About a third of participants would prescribe benzodiazepines, primarily lorazepam. While the use of lorazepam may be indicated with the clinical presentation of catatonia symptoms [Reference Rogers, Oldham, Fricchione, Northoff, Ellen Wilson and Mann46] identified by 13% of participants, the use of benzodiazepines is still high, especially considering the lack of evidence for their efficacy in treating psychotic symptoms and existing evidence of side effects [Reference Zaman, Sampson, Beck, Sharma, Clay and Spyridi47]. The high use of benzodiazepines is consistent with studies from Eastern Europe, indicating high numbers of patients with schizophrenia treated with benzodiazepines for lengthy periods of time [Reference Maric, Andric Petrovic, Russo, Jerotic, Ristic and Savić48]. However, the high use of benzodiazepines seems to be a widespread clinical practice, unrelated to a specific disorder, as was also previously identified as a treatment preference for PTSD in Central European and Southern European countries [Reference Rojnic Kuzman, Padberg, Amann, Schouler-Ocak, Bajic and Melartin24]. While some studies have suggested that benzodiazepine use is more widespread in Western countries [Reference Bushnell, Stürmer, Gaynes, Pate and Miller49, 50], there may be a lack of data from Central European countries, as pointed out by some authors. [Reference Winkler, Krupchanka, Roberts, Kondratova, Machů and Höschl51]
Almost two-thirds would consider therapeutic drug monitoring (TDM), even when there is no indication of resistance to treatment, non-compliance, or adverse reactions, which are the major indications for TDM according to guidelines [Reference Falkai, Wagner, John, Yakimov, Galderisi and Bitter20, Reference Hiemke, Bergemann, Clement, Conca, Deckert and Domschke39] Interestingly, about half would consider long-acting injectables (LAIs), which is in line with the EPA guidance on the pharmacological treatment of schizophrenia [Reference Falkai, Wagner, John, Yakimov, Galderisi and Bitter20] and recent clinical consensus [Reference Arango, Fagiolini, Gorwood, Kane, Diaz-Mendoza and Sahota52]. This may reflect a trend towards increasing prescription of LAIs, as they were found to be more efficacious in relapse prevention compared to oral formulations [Reference Barnes, Shingleton-Smith and Paton53, Reference Arango, Baeza, Bernardo, Cañas, de Dios and Díaz-Marsá54]. However, this percentage seems rather low compared to the United States [Reference Bunting, Chalmers, Yohanna and Lee55] where up to 60% of patients with first-episode psychosis are prescribed LAIs, but with considerable variation – in community-based settings with specialized programmes, the use of LAIs is higher compared to hospital-based care.
Case B: Prodromal stage/high-risk states
The relatively low number of participants correctly identifying “attenuated psychosis syndrome” may reflect the combination of two interrelated issues: (1) the currently undefined diagnostic status of prodromal schizophrenia in major classification systems, and (2) the broader challenge of relatively modest diagnostic precision when assessing psychosis-risk syndromes in real-world clinical vignettes, even by international leading experts (as evidenced by recent research [Reference Urkin, Parnas, Raballo and Koren56]).
Concordantly with the low number of participants who correctly identified the “attenuated psychosis syndrome,” only about 15% of participants would use risk assessment scales, reflecting that take-up of appropriate assessment tools was far lower than the EPA recommendation, which states that any psychosis-preventive intervention requires full assessment of the clinical high risk (CHR) status in accordance with the EPA guidance on early detection of psychosis [Reference Schmidt, Schultze-Lutter, Schimmelmann, Maric, Salokangas and Riecher-Rössler35].
Interestingly, disregarding confusion about the concept or diagnostic scales, the use of antipsychotics was, in general, in line with the guidelines, as about a third stated they would not use any antipsychotics or did not mark any, and those who prescribed would use second-generation antipsychotics. However, the “low-dose formulation” may be particularly difficult to grasp in clinical practice, especially for some of the medications. The use of other medications, especially antidepressants, was in line with the guidelines.
Case C: Negative and cognitive symptoms
Overall, these results follow the recommendation of the EPA guidance on the treatment of negative symptoms to use antipsychotics with antidepressant properties and add-on antidepressant treatment. To avoid polypharmacy, however, the add-on antidepressant should be discontinued if it does not lead to improvement in negative symptoms and/or depression [Reference Galderisi, Kaiser, Bitter, Nordentoft, Mucci and Sabé31]. In the case of specific antipsychotics, most participants would choose aripiprazole, cariprazine, and, more rarely, risperidone. This can be considered in line with the EPA guidance on the treatment of negative symptoms in schizophrenia, which suggests the use of amisulpride and cariprazine for negative symptoms, but with the notion that further research is necessary before a specific recommendation can be provided [Reference Galderisi, Kaiser, Bitter, Nordentoft, Mucci and Sabé31]. This is also in line with the head-to-head comparison of antipsychotics, where second-generation antipsychotics were associated with fewer negative symptoms than first-generation antipsychotics [Reference Leucht, Corves, Arbter, Engel, Li and Davis57], although both haloperidol and risperidone can induce negative symptoms in healthy individuals [Reference Artaloytia, Arango, Lahti, Sanz, Pascual and Cubero58].
There was very low consensus among participants in the choice of specific add-on antidepressants, and concordantly, there is no specific recommendation on the use of antidepressants in the EPA guidance on the treatment of negative symptoms in schizophrenia [Reference Galderisi, Kaiser, Bitter, Nordentoft, Mucci and Sabé31], nor in SIGN recommendations [16]. Therefore, considering the multitude of antidepressants, a call for more specific add-on strategy recommendations may be appropriate. Possible beneficial effects were found by augmentation with antidepressants [Reference Galling, Roldán, Hagi, Rietschel, Walyzada and Zheng59] where 12 combinations outperformed monotherapy, with Serotonine and Norepinephrine Reuptake Inhibitors (SNRIs) associated with the largest effect size. In a report encompassing 82 add-on studies, Selective Serotonin Reuptake Inhibitors (SSRIs) and tetracyclic antidepressants were more efficacious than control, but individually, selegiline, duloxetine, citalopram, fluvoxamine, and mirtazapine appeared significantly more efficacious than monotherapy for negative symptoms [Reference Falkai, Wagner, John, Yakimov, Galderisi and Bitter20, Reference Correll, Rubio, Inczedy-Farkas, Birnbaum, Kane and Leucht60, Reference Helfer, Samara, Huhn, Klupp, Leucht and Zhu61], although not for the primary negative symptoms [Reference Arango, Garibaldi and Marder62, Reference Galderisi, Mucci, Buchanan and Arango63].
Contrary to guidelines and the results of our study, in the European guidance papers [Reference Falkai, Wagner, John, Yakimov, Galderisi and Bitter20], concordance with the two similar recommendations on the treatment for negative symptoms, “we suggest offering amisulpride (at a low dose) or olanzapine; we suggest avoiding the use of strong D2 receptor blockers by using antipsychotics with a suitable profile or avoiding high-dose treatments,” and “In case of inadequate response to antipsychotic monotherapy, we suggest offering additional treatment with antidepressants to people with schizophrenia and predominant negative symptoms,” reached only 30 and 52.2%, respectively, further indicating variable clinical practice.
Finally, these results are in line with the existing EPA guidance on treatment of cognitive impairment, where it is stated that benzodiazepines have a clearly negative effect on cognition and should be avoided [Reference Vita, Gaebel, Mucci, Sachs, Barlati and Giordano30, Reference Fond, Berna, Boyer, Godin, Brunel and Andrianarisoa64].
Case D: Pregnancy
Our results indicate that clinical practice differs from the international guidelines, as more than a third stated they would not prescribe any antipsychotics. This is contrary to guideline recommendations against stopping antipsychotic medication and stating that antipsychotics do not pose significant risks for pregnancy, supported by studies where patients with treated mental illness are compared to patients with untreated mental illness [Reference Betcher, Montiel and Clark65]. On the other hand, the majority of participants who would continue antipsychotic medication recommend the continuation of the current antipsychotic (in this case, aripiprazole), which proved effective and is in line with the guidelines. Concordant with our results, in the United States, aripiprazole is one of the most frequently prescribed antipsychotics in pregnancy, while in older studies, haloperidol, olanzapine, and risperidone were the most prescribed [Reference Park, Huybrechts, Cohen, Bateman, Desai and Patorno66].
About a third would consider TDM, as indicated by the Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology [Reference Hiemke, Bergemann, Clement, Conca, Deckert and Domschke39], indicating partial concordance with the guideline’s recommendations.
Case E: Treatment resistance
There is considerable variation in definitions of treatment resistance in both research and clinical settings. According to APA guidelines [Reference Keepers, Fochtmann, Anzia, Benjamin, Lyness and Mojtabai29], in terms of treatment adequacy, at least two trials with two different antipsychotics for 6 weeks and adherence of at least 80%, with at least one antipsychotic blood level to assess adherence, are required, including evaluating adherence from at least two sources and obtaining information on prior treatment as well. In clinical (not research) settings, at least two trials of 6 weeks each in adequate clinical doses are required. However, if there is no significant improvement after a few weeks of treatment (e.g., 20% reduction in symptoms), the likelihood of adequate treatment response is minimal, and, often in clinical practice, a faster switch of antipsychotics may occur [Reference Howes, Vergunst, Gee, McGuire, Kapur and Taylor67, Reference Agid, Arenovich, Sajeev, Zipursky, Kapur and Foussias68]. Concordantly, in our study, the median (iqi) switch would happen after 4 (3–6) weeks. Interestingly, one of the statements in the European guidance of pharmacological treatment of schizophrenia [Reference Falkai, Wagner, John, Yakimov, Galderisi and Bitter20] that did not reach clinical consensus at the level of 75% (agreement was 67.5%) was “We recommend evaluating the response status after two weeks (at the latest after four weeks) by using a suitable scale (ideal: PANSS, BPRS; easier: CGI). In case of lack of response (CGI unchanged or worse [CGI < 3]) despite adequate dosing and after excluding secondary causes, we recommend offering the patient a switch to an antipsychotic with a different receptor binding profile, with the aim to achieve response,” indicating variability when it comes to the clinical definition of resistance to treatment.
Guidelines consistently stress the importance of excluding pseudo-resistance and non-adherence. In line with this recommendation, most would probably or certainly consider TDM and screening for substance drug use, and the use of LAIs in the majority of cases.
While the use of clozapine is indicated in treatment-resistant schizophrenia in several guidelines, fewer than half of participants would recommend clozapine, and more often would try a combination of two or even three further antipsychotics. It was noted that barriers to the use of clozapine include the overestimation of its side effects and a lack of knowledge and experience in prescribing [Reference Howes, Vergunst, Gee, McGuire, Kapur and Taylor67, Reference Farooq, Choudry, Cohen, Naeem and Ayub69], although its use in first episode psychosis has been suggested even before two 4-week trials have failed, due to significant improvement and lower rates of re-admittance with clozapine compared with other antipsychotics [Reference Tiihonen, Haukka, Taylor, Haddad, Patel and Korhonen70].
Augmentation with other medications was recommended by half the participants, but distributed evenly between medications, probably indicating a lack of (clinical) evidence for effective augmentation strategies.
Case F: Metabolic syndrome
More than 75% of participants would choose a strategy to replace the antipsychotic associated with metabolic changes with one with a lower propensity to gain weight and metabolic disturbances [Reference Pillinger, McCutcheon, Vano, Mizuno, Arumuham and Hindley71]. This is not the main strategy recommended in the guidelines. While the use of metformin is recommended only for very-high-risk individuals (Case F would qualify for this recommendation), only 16% of participants would recommend metformin, possibly indicating an unwillingness or lack of expertise among psychiatrists to recommend non-psychiatric medication. Indeed, in the European guidance on the pharmacological treatment of schizophrenia [Reference Falkai, Wagner, John, Yakimov, Galderisi and Bitter20], the statement “If there is strong weight gain and it is necessary to continue the current antipsychotic medication, after performing the specified psychotherapeutic and psychosocial interventions, we recommend offering treatment with metformin (first choice) or topiramate (second choice) for weight reduction, taking into account the risks of an additional drug treatment” did not reach the 75% of consensus, despite the good quality scientific evidence.
Psychotherapy, sociotherapy, and recovery-oriented care
Despite psychotherapy (predominantly CBT and family therapy) being consistently recommended in the guidelines during all phases of schizophrenia, it was recommended relatively infrequently in this study. It can be considered at best as only partially in line with the guidelines. Other psychotherapies were recommended even less frequently, making psychological interventions an underused treatment modality.
Psychoeducation and lifestyle recommendations (diet, sleep, smoking, alcohol, drugs, and physical activities) were most often suggested, reaching about 50–60% depending on the case. However, a structured physical health training programme (exercise), which is strongly recommended in the guidelines for the management of cognitive and negative symptoms, as well as being a core part of preventing and managing poor physical health in people with Severe Mental Illness (SMI) [Reference Vita, Gaebel, Mucci, Sachs, Barlati and Giordano30, Reference Stubbs, Vancampfort, Hallgren, Firth, Veronese and Solmi33, Reference Maurus, Wagner, Spaeth, Vogel, Muenz and Seitz34] was endorsed in only about 30% of cases involving antipsychotic-induced metabolic side effects and in 24% of cases describing cognitive and negative symptoms.
Creative therapies were suggested in 20% of cases. These therapies are generally supported by the guidelines, but quite non-specifically or not universally. For example, while the use of art therapy in the treatment of negative symptoms is supported by NICE guidelines [17], it is not supported in other guidelines, leaving the evidence on its efficacy as inconclusive [Reference Laws and Conway73].
Cognitive remediation, which is largely supported for the treatment of cognitive symptoms, was recommended by fewer than 15%, possibly indicating a relative unavailability or lack of experience [Reference Keepers, Fochtmann, Anzia, Benjamin, Lyness and Mojtabai29, Reference Vita, Gaebel, Mucci, Sachs, Barlati and Giordano30].
Support from psychiatric services
The low use of non-pharmacological treatment in all cases cannot be considered in line with guidelines, as these consistently recommend psychotherapy and interventions aimed at recovery within services for persons with schizophrenia during all phases of the illness [17, Reference Keepers, Fochtmann, Anzia, Benjamin, Lyness and Mojtabai29].
Considering that only up to 50% would recommend the use of recovery-oriented care, it seems that recovery-oriented care is not supported within the organizational framework of psychiatric services across Europe. A community mental health model providing these services should be fostered across Europe. At the moment, community-based services are still developing in many European countries, while hospital-based services remain the predominant model of care [Reference Winkler, Krupchanka, Roberts, Kondratova, Machů and Höschl51, Reference Semrau, Barley, Law and Thornicroft74].
A relative lack of psychotherapists across Europe, possibly indicating the need to improve the provision of psychotherapy training as part of psychiatric training across Europe [Reference Fiorillo, Luciano, Giacco, Del Vecchio, Baldass and De Vriendt75], may be reflected in only up to 25% of participants recommending psychotherapy, except in the case of describing a person in prodrome. Alternatively, it is possible that psychotherapy is more often offered to younger patients within specialized services, such as early intervention services. Indeed, guidelines specifically recommend the use of other sociotherapy and recovery-oriented care as part of early intervention services for first-episode psychosis and persons experiencing prodromal symptoms [17]. These are offered across Europe and worldwide [Reference Maric, Raballo, Rojnic Kuzman, Andric Petrovic, Klosterkötter and Riecher-Rössler76, Reference Kotlicka-Antczak, Podgórski, Oliver, Maric, Valmaggia and Fusar-Poli77] and include a wide and variable range of services, from psychopharmacology to psychosocial interventions. However, it seems that the pathway to care for people at risk is not straightforward, even in countries where these services exist. Persons at clinically high risk may be treated within other services (e.g., in services for children and adolescents, youth services, general practitioners, or general psychiatric services) [Reference Kotlicka-Antczak, Podgórski, Oliver, Maric, Valmaggia and Fusar-Poli77, 78], suggesting that better provision of intervention services should be encouraged across the European Union countries.
Finally, during pregnancy, referral to perinatal services is suggested [79]. While some European countries have established perinatal psychiatry services, there remains a significant need for the development and implementation of comprehensive perinatal mental health care across the continent [Reference Horakova, Nemcova, Hrdlickova, Kalli, Davletova and Duarte80].
Limitations of the study
The study had several limitations, which have been described elsewhere [Reference Rojnic Kuzman, Padberg, Amann, Schouler-Ocak, Bajic and Melartin24]. Briefly, we cannot claim that the sample is fully representative at the national level because of low response rates in individual countries and a possible association of non-response with specific preferred treatment approaches. The overall number of participants comprised a small proportion of all psychiatrists, and the analysis was done at the whole sample level, not taking potential regional differences into account. Second, considering that about half of the participants worked in university hospitals and have a PhD, the sample could be biased towards clinicians focused on research and more likely to follow guidelines (that they produce) compared to clinicians working outside university centres. Third, in the sample, there was a high proportion of psychotherapists trained in CBT, which could have biased some of the responses and may reflect the variability in availability and training across Europe [Reference Fiorillo, Luciano, Giacco, Del Vecchio, Baldass and De Vriendt75]. Fourth, this study used a non-standardized tool to measure treatment attitudes based on clinical cases. Although case vignettes are frequently used to assess clinical judgments made by health professionals on “real-world” phenomena, and were developed following a set of recommendations to ensure both internal and external validity [Reference Falkai, Wagner, John, Yakimov, Galderisi and Bitter20], the responses were standardized for treatment options only, and not for assessing diagnostic precision and differential diagnostic competencies. Additionally, case vignettes were administered in English, which may have reduced clarity due to potential language barriers.
Furthermore, the selection of analysed guidelines assumed that European guidance papers, along with selected international guidelines (e.g., APA guidelines), have a greater influence on psychiatric practice in Europe, which was confirmed by the results summarized in Supplementary Table 3. Second, we assumed that national guidelines, where available, are largely aligned with these broader guidelines. Finally, the selection was also limited by language constraints, as only English-language guidelines were considered. However, it is interesting to note that 5–20% of participants reported that they do not use guidelines in clinical practice, although this percentage was much lower compared to the results obtained from the Ambassador study on PTSD, where non-use of guidance reached about 50% [Reference Rojnic Kuzman, Padberg, Amann, Schouler-Ocak, Bajic and Melartin24]. Possibly, this correctly reflects practice in the field of schizophrenia compared to other fields.
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