ࡱ> q`(bjbjqPqP7::z''''D(DO2,)6b*b*b*z*U+U+U+bdddddd$h1U+U+11b*z*  ? ? ?1 b*z*b ?1b ? ?6TX2[b* ) ';Yb0OZ<282[2[tH U+, ?-.U+U+U+? U+U+U+O1111 Comparison of Recommendations on Psychopharmacotherapy from Guidelines for Treatment of Schizophrenia Type of publication: review Oliver Kozumplik1, Suzana Uzun1 and Miro Jakovljevi2,3 1University Department, Psychiatric Hospital Vrapce, Zagreb, Croatia 2University Department of Psychiatry, Clinical Hospital Center Zagreb, Zagreb, Croatia 3School of Medicine, University of Zagreb, Zagreb, Croatia Treatment Guidelines for Schizophrenia A B S T R A C T The aim of this article was to analyse and compare recommendations from guidelines for treatment of schizophrenia on psychopharmacotherapy of schizophrenia. The guidelines were analysed and compared regarding the initiatiation of antipsychotic treatment, the first choice antipsychotic in the first episode of schizophrenia, the daily dosage of antipsychotic in the first episode of schizophrenia, initiation of treatment with a single antipsychotic, introduction of clozapine in therapy, continuous dosing strategies or intermittent-dose strategies, medications in case of nonadherence, recommendations in case of treatment resistance, and initiation of antidepressant treatment. The investigated guidelines recommend that the treatment of psychotic episode should start as soon as possible, and that atypical antipsychotics (except clozapine) should be the first line of treatment during first episode of schizophrenia. The recommended daily dosages are between 300 and 1000 mg chlorpromazine equivalents for the first-generation antipsychotics in the treatment of an acute symptom episode for a minimum of 6 weeks, whereby the minimum effective dose should be used. Treatment should be initiated and continued with a single antipsychotic, except during short periods of overlap in the case of switching, and in the cases of treatment resistance. Guidelines recommend clozapine as treatment of choice for treatment-resistant schizophrenia. Targeted, intermittent dosage maintenance strategies should not be used routinely in lieu of continuous dosage regimens because of the increased risk of symptom worsening or relapse. In case of nonadherence long-acting injectable antipsychotic medication should be considered. Antidepressants may be added as an adjunct to antipsychotics when syndromal criteria for major depressive episode are met. In conclusion, the investigation showed vast similarities between recommendations from the five investigated guidelines for treatment of schizophrenia, with more differences in the extent of recomendations regarding particular investigated treatment issues. Key words: schizophrenia, psychosis, antipsychotics, antidepressants, side effects Introduction Schizophrenia is a mental illness that affects individuals, but also their families, caregivers and society. Modern treatment of schizophrenia comprises integrative application of psychopharmacological, psychosocial and psychotherapeutic interventions1. Guidelines for treatment of schizophrenia are developed in many countries of the World, today. Clinical guidelines, defined as 'systematically developed statements to assist both practitioner and patient decisions in specific circumstances', have become an increasingly familiar part of clinical care. Guidelines are viewed as useful tools for making care more consistent and efficient and for closing the gap between what clinicians do and what scientific evidence supports2 Evidence based psychiatry and treatment guidelines have a significant role in raising the quality of mental health care and treatment, as well as in providing order where chaos reigns. The purpose of treatment guidelines and algorithms is to provide psychiatrists, health authorities, patients and their families with best evidence for making treatment decisions3. These recommendations are meant to provide a framework for clinical decision making, not to replace clinical judgment. As with any algorithm, treatment practices will evolve beyond the recommendations of this consensus conference as new evidence and additional medications become available4. The aim of this article was to analyse and compare recommendations from guidelines for treatment of schizophrenia on psychopharmacotherapy of schizophrenia. Materials and Methods The research included content analysis and comparation of recommendations from guidelines for treatment of schizophrenia regarding psychopharmacotherapy of schizophrenia. Recommendations from the following guidelines were considered: American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, 2nd ed.5; Canadian Psychiatric Association Working Group Members. Clinical Practice Guidelines Treatment of Schizophrenia6; National Institute for Clinical Excellence. Guidance on the use of newer (atypical) antipsychotic drugs for the treatment of schizophrenia7; Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for the Treatment of Schizophrenia and Related Disorders. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of schizophrenia and related disorders8; World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia. WFSBP Guidelines for Biological Treatment of Schizophrenia, Part 1: Acute treatment of schizophrenia9. The guidelines were compared with respect to the following: 1. When to initiate antipsychotic treatment? 2. Which antipsychotic should be the first choice for treatment in the first episode of schizophrenia? 3. Which is the recommended daily dosage of an antipsychotic in the first episode of schizophrenia? 4. Is it recommended to initiate treatment with a single antipsychotic? 5. When to introduce clozapine in therapy? 6. Continuous dosing strategies or intermittent-dose strategies? 7. Which medications are recommended in case of nonadherence? 8. What is recommended in case of treatment resistance? 9. When to initiate antidepressant treatment? Results 1. When to initiate antipsychotic treatment? The investigated guidelines recommend that the treatment of psychotic episode should start as soon as possible. A patient with a first episode of symptoms characterizing schizophrenia may be experiencing a schizophrenic episode or the onset of schizophreniform disorder, or may be having an episode of another illness or disorder that can cause similar symptoms. Therefore careful initial evaluation and assessment has to be conducted9. In persons who meet the criteria for being prodromally symptomatic and at risk for psychosis in the near future, careful assessment and frequent monitoring are recommended until symptoms remit spontaneously, evolve into schizophrenia, or evolve into another diagnosable and treatable mental disorder5. The possibility of psychotic disorder should be carefully considered in any young person who is becoming more socially withdrawn, performing more poorly for a sustained period of time at school or at work, behaving in an unusual manner for them, or becoming distressed or agitated yet may be unable to explain why. If subthreshold psychotic features combined with the onset of disability indicating ultra-high risk are present, the young person and their relatives should be assessed and mental state and safety monitored regularly (every 24 weeks) in a context of ongoing support8. Patients who meet criteria for ultra high-risk mental state for psychosis should be offered monitoring for at least 1 to 2 years; if clinically indicated, they may be offered supportive therapy and symptomatic treatment for emerging psychotic symptoms, depression, or anxiety6. Antipsychotic medications should not normally be prescribed unless at least 1 week of frank positive psychotic symptoms have been sustained. The exception may be where briefer or milder positive symptoms are directly associated with risk of self-harm or aggression8. In the acute treatment phase, the main emphasis is on pharmacotherapeutic (and other somatic) interventions. Therefore antipsychotic therapy should be initiated as a necessary part of a comprehensive package of care that addresses the individuals clinical, emotional and social needs9. Where there are acute symptoms of schizophrenia, the general practitioner (GP) should consider starting atypical antipsychotic drugs at the earliest opportunity before the individual is seen by a psychiatrist, if necessary. Wherever possible, this should be following discussion with a psychiatrist and referral should be a matter of urgency7. It is recommended that pharmacological treatment should be initiated promptly, because acute psychotic exacerbations are associated with emotional distress, and a substantial risk of dangerous behaviours9. 2. Which antipsychotic should be the first choice for treatment in the first episode of schizophrenia? The investigated guidelines agree that atypical antipsychotics (except clozapine) should be first line of treatment during first episode of schizophrenia, because of better tolerability and lower risk for extrapyramidal symptoms (EPS), especially tardive diskinesia5,7-9 compared to typical antipsychotics. Second-generation antipsychotics (SGAs) (or atypical antipsychotics) are indicated mostly due to better tolerability and lower risk of EPS, especially tardive dyskinesia5-9. However, there is no recommendation about which specific antipsychotic the treatment should be initiated with. Direct comparisons between atypical antipsychotics are needed to establish their respective risk/benefit profiles. Trials should pay particular attention to the long-term benefits and risks of the drugs, including diabetes, weight gain and quality of life7. 3. Which is the recommended daily dosage of antipsychotic in the first episode of schizophrenia? The recommended daily dosages are between 300 and 1000 mg chlorpromazine equivalents for the first-generation antipsychotics (FGAs) in the treatment of an acute symptom episode for a minimum of 6 weeks5-7,9, whereby the minimum effective dose should be used. The optimal dose for each patient has to be found by clinical judgment, but generally guidelines recommend antipsychotic therapy at the lower end of the standard dose range5,7. In first-episode psychosis, dosages should be started in the lower half of the treatment range6. Especially when using FGAs it is recommended to keep the dose as low as possible to reduce the risk of extrapyramidal side effects9. The recommended dose is that which is both effective and not likely to cause side effects that are subjectively difficult to tolerate, since the experience of unpleasant side effects may affect long-term adherence. The dose may be titrated as quickly as tolerated to the target therapeutic dose of the antipsychotic medication, and unless there is evidence that the patient is having uncomfortable side effects, monitoring of the patients clinical status for 24 weeks is warranted to evaluate the patients response to the treatment. During these weeks it is often important for physicians to be patient and avoid the temptation to prematurely escalate the dose for patients who are responding slowly5. Initial dosage should be low and increased slowly at spaced intervals only if response is slow or incomplete. Such doses will probably not have much early effect (within the first few days) on distress, insomnia and behavioural disturbances secondary to the psychosis, so skilled nursing care, a safe and supportive environment, and regular and sufficient doses of benzodiazepines are all essential interim components of management8. Rapid dose escalation, high loading doses and treatment with high doses above the mentioned dose range do not have proven superior efficacy, but have been associated with increased side effects9. 4. Is it recommended to initiate treatment with a single antipsychotic? Guidelines agree in the recommendation that the treatment should be initiated and continued with a single antipsychotic. The exceptions to this recommendation are short periods of overlap in the case of switching5-8, and the cases of treatment resistance5-7. Using more than one antipsychotic simultaneously is not supported by available evidence6. In clinical practice it may be useful to select the antipsychotic with which the best previous response could be obtained for further combination9. Clinicians should be aware of potentiating side effects when combining two or more antipsychotics and may select agents with decreased interaction risk9. 5. When to introduce clozapine in therapy? Guidelines recommend clozapine as treatment of choice for treatment-resistant schizophrenia because of its efficacy in this regard5-9. According to clinical practice a target dose of up to 400 mg/day may be selected. After nonreponse, despite continuing treatment over 4-6 weeks and obtaining sufficient blood levels of clozapine, the next step should consist of increasing the dosage up to 900 mg/day and closely monitoring for adverse effects9. Given clozapines superior efficacy, a clozapine trial should be considered for a patient with persistent suicidal ideation or behavior that has not responded to other treatments. Clozapine is the most extensively studied and has been shown to reduce the rates of suicide and persistent suicidal behavior. Clozapine may be considered for patients with persistent hostility and aggression, given that superior efficacy of clozapine has been demonstrated in these patient populations5. Early clozapine use should be considered if suicide risk is prominent or persistent, despite treatment for depression, if such treatment is ineffective, or if depression is not prominent8. Persistent aggressivity may be helped by a trial of clozapine. Persistent suicidal thoughts or behaviours are an indication that clozapine should be considered6. SGAs, especially clozapine reveal efficacy in the treatment of hostility and aggressive behaviour9. SGAs may be recommended as first-line treatment in patients with schizophrenia and comorbid substance use disorder; it may be favourable for patients with this dual diagnosis to lower the threshold for recommending a trial with clozapine than in patients without comorbid substance use disorder9. 6. Continuous dosing strategies or intermittent-dose strategies? Targeted, intermittent dosage maintenance strategies should not be used routinely in lieu of continuous dosage regimens because of the increased risk of symptom worsening or relapse7. If the patient has improved with a particular medication regimen, continuation of that regimen and monitoring are recommended for at least 6 months. Premature lowering of dose or discontinuation of medication during this phase may lead to a recurrence of symptoms and possible relapse5. In case of first episode psychosis, in fully remitted patients, antipsychotic medication should be continued for at least 12 months if possible and then an attempt made to withdraw the medication over a period of at least several weeks. Close follow up should be continued with specialist review for a further period of 12 months beyond this and any relapse rapidly identified and treated. Patients should not be discharged to sole primary care during this phase, though shared care is optimal at all stages8. Premature discontinuation or reduction of antipsychotic medication during stabilization phase places the patient at high risk for relapse. Assessments should take place at least every 3 months during stable phase to achieve optimal dosages and choice of antipsychotic medications and to monitor for drug-induced side effects. There are no predictive factors indicating which patients can safely and permanently discontinue antipsychotic medication. Antipsychotic medication for the treatment of a first-episode psychosis should be continued for a minimum of 2 years following first recovery of symptoms. There is evidence to suggest that the risk of relapse is greatest in the first 5 years6. 7. Which medications are recommended in case of nonadherence? If nonadherence is suspected, it is recommended that the reasons for it be evaluated and considered in the treatment plan5,9. The analysed treatment guidelines agree that in case of nonadherence long-acting injectable antipsychotic medication should be considered5-9. 8. What is recommended in case of treatment resistance? The investigated guidelines recommend clozapine as treatment of choice for treatment-resistant schizophrenia because of its efficacy in this regard5-9. If the patient is not improving, it may be helpful to establish whether the lack of response can be explained by medication nonadherence, rapid medication metabolism, or poor absorption. In assessing treatment resistance or partial response, it is important to carefully evaluate whether the patient has had an adequate trial of an antipsychotic medication, including whether the dose is adequate and whether the patient has been taking the medication as prescribed. An initial trial of 46 weeks generally is needed to determine if the patient will have any symptomatic response, and symptoms can continue to improve over 6 months or even longer periods of antipsychotic treatment5. The first step in the clinical management of treatment resistant schizophrenia (TRS) is to establish that antipsychotic drugs have been adequately tried in terms of dosage, duration and adherence. Other causes of non-response should be considered in the clinical assessment, such as comorbid substance misuse, poor treatment adherence, the concurrent use of other prescribed medicines and physical illness. TRS is suggested by a lack of satisfactory clinical improvement despite the sequential use of the recommended doses for 6 to 8 weeks of at least two antipsychotics, at least one of which should be an atypical. However, the addition of a second antipsychotic to clozapine may be considered for people with TRS for whom clozapine alone has proved insufficiently effective7. TRS is defined as the failure of full remission of positive symptoms or the lack of satisfactory clinical improvement despite sequential use of recommended doses of two or more antipsychotic medications for 68 weeks. If treatment resistance persists despite clozapine, the most effective prior drug should be reinstated and an appropriate adjunctive therapy, such as lithium, added. There is little evidence that combining antipsychotic medications is useful; conversely this increases the side-effect burden. Symptoms may persist but often wax and wane, and can still be compatible with good quality of life even if they are at times severe8. In individuals with clearly defined TRS, in case of nonresponse to clozapine treatment alternatives may be other SGAs, augmentation strategies (antidepressants, mood stabilisers) in relation to target symptoms, combination of antipsychotics (limited evidence for risperidone or sulpiride in combination with clozapine) and, as the last treatment option, electroconvulsive therapy (ECT)9. 9. When to initiate antidepressant treatment? Beside the above mentioned therapy with antidepressants in case of TRS, treatment with antidepressants added as an adjunct to antipsychotics is indicated when the symptoms meet the syndromal criteria for major depressive disorder or are severe and causing significant distress (e.g., when accompanied by suicidal ideation) or interfering with function. When prescribed, antidepressants are used in the same doses that are used for treatment of major depressive disorder. Symptom dimensions such as mania and severe depression require specific treatment with mood stabilizers and antidepressants. Pharmacological treatments should be introduced with great care in drug-naive patients with the overriding principle of doing the least harm while aiming for maximum benefit. This means the graded introduction with careful explanation of low dose antipsychotic medication along with antimanic or antidepressant medication when these syndromes are present. Such doses will probably not have much early effect (within the first few days) on distress, insomnia and behavioural disturbances secondary to the psychosis, so skilled nursing care, a safe and supportive environment, and regular and sufficient doses of benzodiazepines are all essential interim components of management8. A major depressive episode in the stable phase of schizophrenia is an indication for a trial of an antidepressant6. Antidepressants may be added as an adjunct to antipsychotics when syndromal criteria for major depressive episode are met5,9. Despite atypical antipsychotic agents, antidepressants are used as adjunctive treatment in patients with predominantly negative symptoms5. The treatment of secondary negative symptoms consists of treating their cause, e.g., antipsychotics for primary positive symptoms, antidepressants for depression, anxiolytics for anxiety disorders, or antiparkinsonian agents or antipsychotic dose reduction for extrapyramidal side effects5. Overall, the evidence for efficacy of antidepressants for negative symptoms of schizophrenia is limited, especially when taking into consideration the fact that differentiating the improvement in depressive symptoms from negative symptoms is difficult in some cases5,9. Polypharmacy, such as combinations of an antipsychotic agent, a mood stabilizer and a benzodiazepine or an antidepressant, may be fully justified by comorbid symptom dimensions, which are extremely common in psychotic disorders8. Discussion and Conclusion The investigation showed vast similarities between recommendations from the five investigated guidelines for treatment of schizophrenia. Some differences have been observed, such as the question of duration of antipsychotics' treatment of a first-episode psychosis following recovery of symptoms, and the question of appropriate therapy in case treatment resistance persists despite therapy with clozapine. Guidelines differed in the extent of recommendations regarding particular issues - for instance regarding management of prodromal symptoms, titration of daily dosage of antipsychotics and introduction of antidepressant treatment. Moreover, not all the questions have been answered by the guidelines' recommendations, revealing new challenges for future researche in the field of psychopharmacotherapy of patients with schizophrenia. For instance, there is no recommendation about which specific antipsychotic the treatment should be initiated with, only the general recommendation giving advantage to atypical antipsychotics over typical antipsychotics, mainly due to side effects' profile. Comparisons of recomendations from guidelines for treatment of schizophrenia were performed in some earlier investigations10-12, focusing on different aspects of treatment. A previous investigation with aim was to systematically compare national schizophrenia guidelines from different countries showed numerous variations between guidelines, including their methodology and content. These variations included pharmacological first-line therapy in acute psychosis, antipsychotic dosage for acute and maintenance treatment, management of side-effects with first-generation antipsychotics, etc. Also, there were strong variations in the type of psychosocial interventions recommended10. In another investigation the authors examined three widely distributed guidelines and one set of algorithms to compare characteristics that are likely to influence implementation, including their degree of scientific rigor, comprehensiveness, and clinical applicability. The three examined guidelines were the Expert Consensus Guideline Series' "Treatment of Schizophrenia"; the APA's "Practice Guideline for the Treatment of Patients With Schizophrenia"; and the Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations. The algorithms are those of the Texas Medication Algorithm Project (TMAP). The analysis of content showed that the APA guideline includes several recommendations about pharmacological management, group and individual therapy, vocational rehabilitation, and specific psychosocial interventions. The PORT recommendations focuse mainly on pharmacotherapy, but recommendations are also made for family interventions, psychological interventions, vocational rehabilitation, and case management. The Expert Consensus guideline addresses both pharmacological and psychosocial interventions and offers recommendations about the intensity or location of nonpharmacological services. In contrast, the TMAP algorithms address only the pharmacological management of schizophrenia11. In the investigation that aimed to review therapeutic ways of management of antipsychotics' side effects, modern guidelines were investigated, as well as recent articles on this subject. The content analysis showed that guidelines agree in the recommendation that side effects should be monitored regularly, and the side effect profile of the prescribed antipsychotic should be considered. Furthermore, in case of unacceptable side effects, changing to a different antipsychotic is recommended12. Beside the challenges already described, there are many other issues regarding treatment guidelines, today. Along with new ideas and knowledge arising from clinical investigations and every day medical practice, professionals are being faced with new challenges. Another problem is that, although there are many guidelines, they are all more or less out of date, and their recommendations often are inconsistent, leaving clinicians uncertain about the definition of acceptable standards of care13. Also, the question of applicability of guidelines recommendation for each individual patient remains, bearing in mind individual characteristics of each patient and each treatment. In conclusion, the investigation showed vast similarities between recommendations from the five investigated guidelines for treatment of schizophrenia. Guidelines differed more in the extent of recomendations regarding particular investigated treatment issues. Not all the questions have been answered by the guidelines' recommendations, revealing new challenges for future researche in the field of psychopharmacotherapy of patients with schizophrenia. R E F E R E N C E S 1. `TRKALJ IVEZI S, FOLNEGOVI `MALC V, MIMICA N, BAJS BJEGOVI M, MAKARI G, BAGARI A, KRPAN I, Lije ni ki vjesnik 123(11-12) (2001) 287. - 2. ECCLES M, MASON J, Health Technol Assess, 5 (2001) 1.  3. JAKOVLJEVIC M, Psychiatr Danub, 19 (2007) 342. 4.  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KOZUMPLIK O, UZUN S, Psychiatr Danub, 21(1) (2009) 95. 13. CONSTANTINE RJ, Curr Psychiatry Rep, 9(4) (2007) 319. O. Kozumplik, MD, PhD University Department, Psychiatric Hospital Vrapce, Bolnicka cesta 32, 10090 Zagreb, Croatia e-mail: okozumplik@hotmail.com ALGORITMI ZA LIJE ENJE SHIZOFRENIJE: USPOREDBA PREPORUKA O PSIHOFARMAKOTERAPIJI S A } E T A K Cilj ovog rada bio je analiza i usporedba preporuka algoritama za lije enje shizofrenije o psihofarmakoterapiji. Algoritmi su analizirani i usporeeni obzirom na po etak tretmana antipsihoticima, antipsihotik prvog izbora u prvoj epizodi shizofrenije, dnevne doze antipsihotika u prvoj epizodi shizofrenije, zapo injanje tretmana jednim antipsihotikom, tretman klozapinom, kontinuiranu ili intermitentnu terapiju, lijekove u slu aju nesuradljivosti, preporuke u slu aju terapijske rezistencije i lije enje antidepresivima. 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Preporu ene dnevne doze su izmeu 300 i 1000 mg ekvivalenata klorpromazina za antipsihotike prve generacije u lije enju akutnih simptoma tijekom barem 6 tjedana, pri emu se preporu a koristiti najmanju u inkovitu dozu. Lije enje bi trebalo zapo eti i nastaviti jednim antipsihotikom, osim u perodima mijenjanja terapije te u slu aju terapijske rezistencije. Algoritmi preporu aju klozapin kao terapiju izbora u slu aju terapijski rezistentne shizofrenije. Intermitentnu terapiju ne bi trebalo rutinski provoditi zbog poveanog rizika od pogoraanja simptoma ili relapsa. U slu aju nesuradljivosti potrebno jeb H .8LNǿҖzrzgz_T_hhmHsHhEmHsHhhT~mHsHhsmHsHhrmHsHh)\mHsHhhhmHsHUhmHsHhhmHsHhh,mHsHhT~\mHsHhjmHsHhjhjmHsHhT~mHsHh5hhmH sH hN*mH sH h?mH sH hfhhmH sH  razmotriti tretman dugodjelujuim oblicima antipsihoti ke terapije. Antidepresivi se mogu uklju iti u terapiju uz antipsihotike kada za zadovoljeni kriteriji za epizodu depresivnog poremeaja. 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