Prevalence of TRS in the literature.
1. Introduction
Despite significant progress in the treatment of schizophrenia in recent decades, the evolution of a large rate of patients suffering from this mental disorder is little influenced by treatment [1]. The management of these patients, so-called treatment resistant, constitutes a public health problem. Indeed, these very symptomatic patients often require long periods of hospitalization [2], and their care consumes a disproportionately large share of total cost management of schizophrenia [3].
Following the renewed interest in clozapine since 1988, thanks to the baseline study on the neuroleptic Kane and al [4], and the development in this period of several explicit criteria defining treatment-resistant schizophrenia (TRS), like those of Kane [4], Dencker and al [5] and Brenner and al [6], some studies have subsequently estimated its prevalence.
The large number and variety of risk factors associated with poor prognosis or poor response to treatment, reported in the literature, suggest that several pathophysiological mechanisms may contribute to the emergence of resistance.
In this work, we tried to shed light on the prevalence of this concept, as well as its risk factors, through a critical review of the literature.
2. Methodology
In our literature review, we conducted a literature search in two databases MEDLINE and PUBMED. We used the following keywords: treatment-resistant, refractory, schizophrenia, prevalence, Correlates, predictors, poor outcome, Treatment refractoriness, Treatment response, poor prognosis.
For studies estimating the prevalence of TRS, we selected the works that have considered the resistance as a categorical diagnosis, defining it by explicit criteria.
For risk factors of TRS, we selected studies that have specifically studied the risk factors of resistance, and the studies that studied the risk factors of poor prognosis or poor response to treatment.
3. Prevalence of treatment-resistant schizophrenia
3.1. Results
The prevalence of resistant schizophrenia ranged from 5 to 60% (Table 1) in the four studies in the literature. Vanelle only found a low rate of 5% resistance because of too restrictive criteria of resistance corresponding to stages 5 and 6 of Dencker and May defining TRS. The results of the other three studies suggest that an important rate of patients do not derive virtually any benefit of treatment and that the TRS is therefore a true public health problem [7]. Many authors agree on the fact that 1/5 to 1/3 of patients are resistant to treatment [1]. Methodological differences between these different studies concerning inclusion criteria and the TRS criteria were important, which explains the wide variation in the estimate of the prevalence of TRS: 5 to 60%. The study by Juarez-Reyes and al [8] illustrates this fact. Applying the criteria of the FDA (Food and Drugs Administration) for the prescription of Clozapine in the United States of America, Juarez-Reyes et al found in their sample a prevalence of 42.9% of resistant patients, but applying the more restrictive criteria of Kane on the same sample, the prevalence dropped to 12.9%.
These methodological differences reflect a lack of consensus on the concept of TRS, which seems to hamper research in this field, since the studies found were few, relatively old and only conducted between 1990 and 1996.
|
|
|
|
|||
|
Retrospective estimates based on three large-scale surveys, of patients in New York State |
unspecified | unspecified | unspecified | BPRS CGI |
.58 % of inpatients and 24 % of outpatients |
|
566 SKZ or SAD inpatients since at least 6 months disease duration since 3 years |
2 | 3 months | .5000 mg/a day | CGI level 5 and 6 of May and Dencker classification of treatment response |
5% |
|
293 SKZ ou SAD | 2 | 4 weeks | 600 mg/a day | BPRS CGI GAF |
42.9 +/- 5.9% |
|
803 SKZ or SAD inpatients since at least 4 months and at least 24 months of hospitalization during the last 5 years disease duration since 5 years |
2 | 6 weeks | .5000 mg/a day | BPRS CGI FDA criteria for eligibility to Clozapine |
60% |
3.2. Discussion of methodological differences
The methodological differences were related to:
3.2.1. Inclusion criteria
Essock [11] required in his sample only inpatients that must have had a total hospitalization of at least 24 months for the preceding 5 years as inclusion criteria. It is clear that in such sample the prevalence of TRS will be overestimated. By applying FDA criteria for eligibility to Clozapine in this sample, Essock found the highest rate of TRS: 60%. Indeed, if outpatients were including in the sample, prevalence of TRS would be less elevated. Essock [11] justified such restrictive inclusion criteria by the fact "to ensure that Clozapine was most available for those most in need", because of the high cost of this treatment, and thus he recognized that he did not screen TRS in all potentially patients in need to Clozapine, such as outpatients.
3.2.2. Criteria of TRS
3.2.2.1. Chronic hospitalization
In Vanelle’s study [10], which is based on the Dencker and May criteria [5] to define the TRS, the need of continuous hospital stay was an essential criterion of resistance. Such highly restrictive criteria of resistance may underestimate TRS. This highly restrictive criterion seems explaining the low rate of TRS in Vanelle’s study 5 % [10]. Currently, most authors agree that chronic hospitalization is not necessary for criteria of TRS [1].
3.2.2.2. Duration criteria
Persistence of illness for more than 5 years was taken as the duration criteria for TRS by Kane et al [4]. This was most probably the impact of serious side effects of clozapine (drug induced agranulocytosis), which made researchers so stringent about duration criteria. Essock [11] fixed this duration at 5 years and Vanelle [10] at 3 years. The other authors did not specify any duration. Currently, most authors agree that waiting such durations are not necessary and a clinical history of persistent psychosis for at least 2 years is sufficient for TRS [6,12]. Some researchers have mentioned that even one year of unresponsiveness to treatment may be an adequate time period [7].
3.2.2.3. Criteria of adequate drug trial
3.2.2.3.1. Duration of adequate drug trial
This duration ranged from 4 weeks to 3 months between the four studies (Table 1). Most authors agree with the fact a period of 4 to 8 weeks is sufficient to evaluate the efficacy of a therapeutic trial [13-17]. Conley [1] recommended in its definition of TRS established in 2001, a period of 4 to 6 weeks, while the NICE (national institute for clinical excellence) recommends a period of 6 to 8 weeks [18]. Nevertheless, some authors as Vannelle [10], Ciapparelli [19] and Lindenmayer [20] consider that a period less than three months is insufficient to assess the efficacy of a therapeutic trial.
This duration must vary according to symptoms taken into account when assessing the therapeutic trial, because the different symptomatic dimensions do not evolve synchronously. If the assessment of treatment response is based on the positive and negative symptoms, a relatively short period seems sufficient. If the dimensions, such as social functioning, occupational functioning, or quality of life, are included in the scope of the evaluation, a longer period of evaluation should be required. However, the functional dimension of schizophrenia is less specific to treatment response as positive or negative symptoms in a clinical trial, as it can be influenced by several factors other than treatment [21,22].
3.2.2.3.2. Adequate dosage of neuroleptic
Despite the variation of this dose (600 to 1000 mg per day of chlorpromazine equivalents) across studies, it was largely sufficient. Indeed, Kane set the minimum threshold dose, in its definition of resistance, to 1000 mg per day of chlorpromazine equivalent [4]. But the results of more recent studies, using the technique of positron emission tomography, showed that a dose of 400 mg of chlorpromazine daily can block 80-90% of dopamine D2 receptors in the nigrostriatal pathway, and an occupancy rate of 60 to 80% of these receptors is sufficient to obtain a response to neuroleptic treatment [23]. In addition It has been reported that higher doses produce no direct therapeutic benefit even in patients who are nonresponsive to therapy [24] and do not improve efficacy in acute treatment [25].This dopamine antagonism is considered the main mechanism of action of typical neuroleptics [23].Currently, most authors such as Barnes[13], McEvedy [13], Dixon [26], Kinon [24], Shalev [27] and Conley [1] consider that doses between 400 and 600 mg per day of chlorpromazine equivalents are sufficient.
3.2.2.4. Adequate number of trials
Terkelsen [9] could not assess the adequacy of previous trials in his study because he constructed retrospective estimation based on three large-scale surveys, conducted in 1987 and 1988, of patients in New York State. The remaining three authors (table 1) agree that the failure of two trials is a criterion of treatment resistance, and not three as Kane had proposed in the beginning in his initial definition of TRS. Indeed, the fact that there was only a 3% response rate to prospective haloperidol treatment and a 4% response rate to double blind chlorpromazine treatment in the Multicenter Clozapine Trial led to the belief that failure of two retrospective drug trials would be as effective as 3 in screening for treatment resistance [4]. Additionally, Kinon and al [24] mentioned that subjects who do not respond to 2 adequate antipsychotic trials (1 retrospective and 1 prospective) have less than 7% chance of responding to another trial. The FDA guidelines on clozapine use state that a patient before being treated with clozapine should have failed to respond to two separate trials of antipsychotics. Several guidelines such as APA (American Psychiatric Association) [28], NICE [18], IPAP (The International Psychopharmacology Algorithm Project) [29], and TMAP (the Texas Medication Algorithm Project) [30] also recommended that the number of trials of other antipsychotics that should precede a clozapine trial is 2. Thus, two drug trial failures are now generally accepted as the criterion for treatment resistance.
3.2.2.5. Scales for evaluating response to treatment
With the exception of the Vanelle’s study, all of the other studies have used the BPRS as the main tool for assessing the clinical response (Table 1). In this scale the positive psychotic symptoms are the most important. The response to neuroleptic treatment was considered adequate if the score in the BPRS reduction ranges from 20 to 30% as suggested in the literature data [31]. Cognition and subjective perspectives or other illness domains again have not been incorporated into definitions of treatment response in TRS in these studies.
However, according to some authors, the definition of resistant schizophrenia must be multidimensional, and the field to assess during a clinical trial should be extended and include, besides the conventional positive and negative symptoms of schizophrenia, cognitive deficits, quality of life, social reintegration, occupational impairments and behavioral problems [32-35]. But these positions are still controversial. This higher level of requirement is motivated by improving in therapeutic arsenal in the field of schizophrenia as the widespread prescription of Second Generation Antipsychotic (SGA), cognitive remediation and several types of psychotherapy that are effective on certain dimensions of schizophrenia.
3.2.2.6. The question of the type of antipsychotic
The four studies were consistent in the type of neuroleptic. During clinical trials of these studies, only conventional neuroleptics (also called first generation antipsychotics: FGA) are used. The results of these studies, therefore, reflect only the resistance of schizophrenia in this type of neuroleptic. Recently, the evidence that second generation antipsychotics (SGA) are somewhat more effective than traditional medications has opened the question of the type of the drug patient should fail [36]. Currently, most authors [37] and guidelines such as APA (American Psychiatric Association) [28], NICE [18], IPAP [29], TMAP (the Texas Medication Algorithm Project) [30] and Clinical Practice Guidelines for the Treatment of Schizophrenia in Adults of the Department of the COMMONWEALTH OF MASSACHUSETTS [38] agree that failure to respond to second generation antipsychotics should precede a clozapine trial. In the Schizophrenia Algorithm of the International Psychopharmacology Algorithm Project (IPAP) [29] patient is regarded to be refractory if he or she failed to respond to monotherapy with Two trials of Two Different SGA (or Two trials with a FGA, if SGAs are not available). Indeed, atypical antipsychotics cause fewer early and late extrapyramidal neurological side effects, improve adherence to treatment, would be more effective than conventional neuroleptics in negative symptoms, cognitive deficits and mood symptoms, and may be effective in some cases resistant to conventional neuroleptics, but without reaching the effectiveness of clozapine for this indication [39].
3.2.2.7. Recommendations for future studies
Since 1996, the last date of study estimating the prevalence of TRS, there have been changes in treatment practices in schizophrenia, such as the widespread prescription of atypical antipsychotics, or more intensive
A period of two years, during which the patient does not improve significantly, and has a poor psychosocial functioning, seems reasonable even without long hospital stay.
During this period, two well-conducted clinical trials have failed. The characteristics of an adequate therapeutic trial would be:
A period of 4 to 6 weeks each,
A dose of 400 to 600 mg equivalent of chlorpromazine to classical neuroleptics
Among the two trials that failed, one should include an atypical antipsychotic.
Even more restrictive criteria, such as Kane, should be reserved for experimental studies evaluating the efficacy of new drugs in resistant schizophrenia.
4. Risk factors of TRS
In this field, the literature is dominated by studies that have examined factors associated with good or poor prognosis or outcome in general, or factors associated with good or poor response to neuroleptic treatment in particular.
4.1. Risk factors related to the patient
The male gender is among the most documented risk factors of poor prognosis [40]. It was also identified specifically as a factor associated with a poor response to neuroleptic treatment for chronic patients and for patients seen during their first psychotic episode, by numerous studies [41]. This male gender predominance in patients with TRS is explained by a greater sensitivity of dopamine receptors to dopamine antagonism of neuroleptics in women, due to the antidopaminergic effect of natural estrogen [42].
The results of studies correlating the early age of onset and poor outcome are consistent [43,44]. This risk factor was associated with greater dysfunction in prospective studies [45], with poor response to neuroleptics [46-48], with an increased risk of re hospitalization [49] and specifically to the resistance [10]. Schizophrenia has a later onset in females than in males and the difference has been found to be about 5 years in most studies [50] suggesting that the association between early age of onset and poor prognosis, is biased by the variable male gender. However, the fact that the difference in age of onset between men and women disappears in patients with TRS in many studies [44] argues for a direct influence, and independently of gender, of age at onset on treatment response. The association between early age of onset and poor outcome reflects a greater neurodevelopmental insult [51] that can be intensified by environmental factors.
In terms of symptoms, severity of negative symptoms was associated with poor response to treatment in many studies [35,52]. Other clinical aspects of schizophrenia were associated with poor prognosis in the literature, as asociality [53] inappropriate or blunted affects [35,53], the low level of premorbid functioning [54], a high degree of minor neurological signs [55], the absence of affective symptoms [56,57], negative formal thought [52], excessive summertime (July) and clustering of birthdates [58], morbid polydypsia [59], and a less severe overall basic symptomatology (before starting treatment) [60].
In the psychological level, insight, poor coping, and some personality traits such as low social skills, a lack of impulse control, and an intolerance of frustration, alogia would be factors of poor response to psychosocial treatment [61-63].
4.2. Family and socio-environmental risk factors
The presence of family history of schizophrenia would be a poor prognostic factor [64]. A high emotional expressiveness in the family environment was related to higher risk of relapses [65]. A history of obstetric complications is more common in patients not responding to neuroleptic treatment [66]. The absence of precipitating factors [35] and a history of substance abuse [67-70] were associated with poor response to treatment.
4.3. Risk factors associated with cognitive deficits
Several literature reviews have summarized the evidence for associations between functional outcome and cognitive deficits [71-73]. These reviews have regarded ranks of functional outcome measures, including measures of skill acquisition in psychosocial rehabilitation treatment, demonstration of ability to solve simulated interpersonal problems, and community (social and occupational) functioning. The reviews indicated consistent and highly significant relationships between ranks of key cognitive constructs such as episodic memory, immediate / working memory, vigilance, and executive functions, and functional outcome in schizophrenia. The effect sizes of these relationships tended to be in the medium to wide range.
According to several studies, the severity of cognitive deficits is equally or more important than positive or negative symptoms to predict prognosis in schizophrenia [74].
4.4. Para clinical risk factors
4.4.1. The data of brain neuroimaging
The ventricular enlargement is the variable most studied in this field. Over the last three decades, earlier computerized tomography and then MRI, cross sectional studies including chronic patients have found an association between ventricular enlargement and poor outcome [75-77]. Several longitudinal studies conducted during periods of 1 to 5 years of chronic patients [78,79] or first psychotic episode patients [77,80] confirmed these structural changes in the brain and found that they were progressive over the course of illness.
For the gray matter, reduction in total volume or located reduction in certain regions such as the frontal, temporal and occipital cortex and ventral thalamus were identified [77]. In addition, volumes of the putamen, especially dorsal and in the right hemisphere, showed increases in patients with better outcomes, whereas putamen volumes in patients with poor outcome did not differ from those in healthy comparison subjects [81]. Expansion of the putamen is known to occur as a result of antipsychotic treatment, so that failure to expand in patients with poor outcome may be related to their resistance to treatment [77].
Abnormalities of white matter located especially at the frontal and temporal lobe of the right hemisphere were associated with poor outcome [77].
The results of longitudinal studies suggest that these brain volume changes seem to be progressive, and occurred at an early stage of the illness [82].
Dynamic neuroimaging data found that lower pre-treatment striatal metabolism predicted better clinical response to neuroleptic treatment and that drug responders showed a greater increase in striatal metabolism after haloperidol therapy [83-85].
4.4.2. The biology data
In the literature, a smaller increase in plasma levels of prolactin [86,87], and a smaller decrease in plasma homovanillic acid [88-91] following administration of neuroleptic, were associated with poor response treatment. A lower baseline plasma levels of homovanillic acid (before the administration of a neuroleptic), was also associated with poor response to treatment [35,92]. A lack of clinical change after administration of amphetamine (central dopamine agonist) was associated with decreased response to antipsychotics [93]. A blunted response of growth hormone after stimulation with apomorphine [94] has been associated with poor prognosis.
All these factors reflect a poorer response to central dopaminergic action of dopamine antagonist antipsychotics. The hyperactivity of central dopaminergic mesolimbic pathway remains the predominant mechanism that explains the positive symptoms of schizophrenia [39].
4.4.3. The data of electrophysiology
The MMN (mismatch negativity) is an early component of auditory evoked potential, recorded after a disruptive auditory stimulus. The peak of MMN occurs after 100 to 150 milliseconds after the stimulus. Abnormally increased MMN amplitude, as well as abnormal MMN topographical distribution, was associated with a poor functional outcome in schizophrenia [95]. These anomalies reflect pre-attentive deficit process (or automatic attention), related to neuropathological changes in the auditory cortex in schizophrenia [95].
4.4.4. The Electrodermal Activity (EDA)
Some studies have found that heightened electrodermal activity, as indicated by frequent orienting responses to innocuous stimuli, elevated skin conductance level (SCL) and frequent nonspecific skin conductance responses (NS-SCR), is associated with most often poor symptomatic, social and occupational outcome in schizophrenic patients [96].
4.5. Risk factors associated with treatment
The initial duration of untreated psychosis, namely the time gap between the onset of psychotic symptoms and first treatment, also called DUP, is among the most studied risk factors for poor outcome during the last 2 decades [97]. Evidence from both retrospective and prospective studies suggests that a longer duration of untreated psychosis in the early stage of schizophrenia is associated with a longer time to remission and a lower level of recovery, a greater likelihood of relapse and a worse overall outcome [98]. Perkins in a recent meta-analysis has retained a total of 43 publications from 28 sites. He found that shorter DUP was associated with greater response to antipsychotic treatment, as measured by severity of global psychopathology, positive symptoms, negative symptoms, and functional outcomes [97].These findings are frequently interpreted as a consequence of a more intense and rapid progression of a neurodegenerative process in the first years of untreated illness [99].
Response to treatment, at least in some cases, appears to decrease over psychotic relapses. As a result patients have lower rates of remission and longer duration to achieve it [100]. Lieberman and colleagues [101] measured time to remission over three successive psychotic episodes and found that the time to reach remission more than tripled between the first and third episode.
Moreover, the absence of a significant and rapid reduction of symptoms during the first days of neuroleptic treatment (3 to 7 days) [60], the dysphoric subjective response type at an initial dose of neuroleptic [60], a bad alliance with the therapist [63], the occurrence of neurological side effects such as parkinsonism [102], akathisia [10] or tardive dyskinesia [102], predict a poor response to treatment.
4.6. Methodological considerations
In our literature review we have considered the factors influencing the prognosis and response to treatment as factors that may explain the resistance. This choice can be criticized. On the one hand, a poor prognosis or a poor response to neuroleptic treatment is not synonymous with therapeutic resistance. On the other hand, the prognosis is a broader concept that the response to treatment and thus the factors influencing prognosis and those influencing treatment response can be inter-related but not necessarily identical [60]. Accordingly, it is important to consider these potential factors of resistance with caution.
Tools for evaluating the response to treatment or prognosis varied widely, limiting their comparability. Consensus specifying tools for assessing treatment response and prognosis in schizophrenia is therefore of great interest for research in this field [60]. The criteria for remission in schizophrenia proposed by Andreasen et al [103] can be a great help for future studies [104].
In this area of research, the results of longitudinal studies examining schizophrenic patients prospectively from their first psychotic episode are more reliable than cross-sectional studies retrospectively examining chronic patients [102]. Indeed, in samples of chronic patients examined retrospectively, there is firstly an overrepresentation of poor responders or patients with less favorable prognosis, and secondly, a greater heterogeneity because these chronic patients are at different stages of the disease and were exposed for varying periods at different neuroleptics. While in samples of patients followed from their first psychotic episode in longitudinal studies, there is a greater representation of the broad spectrum of response to treatment or prognosis, and a greater homogeneity because patients are at the same stages of the disease (the first months or years of illness) and the exposure to neuroleptics was controlled [102].
Some risk factors of TRS are known to be interrelated, like poor premorbid sociosexual functioning [77] and cognitive deficits that are related to severity of the negative symptoms. At end of design studies with methodological rigor use of statistical techniques such as multiple regression and the development of more complex predictive models is needed for future studies in this area.
4.7. The pathophysiology of TRS
The pathophysiology of TRS is still unclear. Some risk factors for TRS cited above as the low level of premorbid adjustment, male gender, severity of primary negative symptoms, the greater frequency of obstetric complications, the high degree of minor neurological signs, and the vulnerability to develop tardive dyskinesia, suggest a neurodevelopmental origin [98]. These neurodevelopmental factors are more frequently found in patients resistant to treatment from the first clinical trial. Moreover, these factors may have an additive effect, i.e. there should be coexistence of a critical number of such factors for there to be resistance [98]. According to some authors [59,105,106] these factors are the characteristics of a more severe subtype of schizophrenia (Kraepelinian schizophrenia) less influenced by neuroleptic treatment.
However, some patients worsen over the course of their illness either because of its progression or because they become less responsive to treatment [101]. Other TRS risk factors mentioned above as DUP, progressive changes in brain volumes in early stage of illness and the deterioration of treatment response over relapses, support the hypothesis that the resistance would be secondary to a neurodegenerative process, which alters the response to treatment in a progressive manner, and not to a static and finished neurodevelopmental process [99]. Candidate’s neurons for the seat of this neurodegeneration include dopaminergic projections to the cortex, and glutamatergic cortico-cortical projections. This neurodegeneration is due to excessive glutamatergic excitation (excitotoxicity) triggered by the disease, involving the NMDA subtype of glutamate receptor that is coupled to an ion channel for calcium. This excessive excitation induces an excess of intracellular calcium, which activates certain intracellular enzymes which dangerously begin to produce free radicals that destroy the cell [39].
For other authors, these two hypotheses, neurodevelopmental and neurodegenerative, are not mutually exclusive, but in fact they are complementary [98]. Each comes at different stages of the disease in the genesis of resistance to treatment. However, the neurodegenerative hypothesis is more optimistic, because it suggests that treatment resistance is not inevitable, it does not follow the law of all or nothing, at least for some patients, and it would be possible to protect patients against the development of resistance to treatment by receiving early effective and continuous treatment.
4.8. The perspectives
Some risk factors for TRS cited in this literature review, are promising and interesting, and require a particular interest in future studies because they offer an more positive and optimistic approach of the concept of TRS.
4.8.1. The initial duration of untreated psychosis
It is a potentially modifiable risk factor, offering hope for effective therapeutic intervention to avoid resistance by shortening this duration. Indeed, some preliminary studies have found that shortening this period is possible by means of early detection programs [107], and that early intervention can favorably influence the prognosis of schizophrenia [108,109]. Additionally, evidence for a neuroprotective effect of some forms of early treatment such as atypical antipsychotics is beginning to emerge. Atypical antipsychotics may counteract some of the progressive deteriorative effects by enhancing synaptic plasticity and cellular resilience [99]. Finally, understanding the mechanism by which duration of untreated psychosis influences prognosis may lead to better understanding of the pathophysiology of schizophrenia and to improved current treatment strategies [97].
4.8.2. Cognitive deficits
Cognitive impairment has emerged as an important new target in schizophrenia therapeutics in light of evidence that cognitive deficits are critically related to the functional of disability that is characteristic of the illness. The cognitive impairment is a risk factor for TRS that is potentially accessible to efficient therapeutic interventions. Indeed, in addition to atypical antipsychotics that are more effective in improving cognitive deficits than classical antipsychotics [39], there is now enough evidence that some rehabilitation therapies such as cognitive remediation - a cognitive computerized training - can change and improve these deficits [110], and thus it is another promising way forward.
4.8.3. Some paraclinical tests
The mismatch negativity (MMN) is an electrophysiological recording that could predict poor outcome in patients with schizophrenia. It has the advantage of being harmless, quick and easy to made, with low cost, and can be coupled with functional neuroimaging (fMRI) to increase its spatial resolution [95,111]. Like the mismatch negativity, research can provide "biomarkers" associated with prognosis or response to treatment. Predicting precociously a poor outcome using such convenient test will give the therapist the opportunity to optimize treatment at the first trial.
4.8.4. The glutamate hypothesis for schizophrenia
The promising findings of researches on the glutamate hypothesis in pathophysiology and treatment of schizophrenia allow hope for having future drugs modulating glutamatergic neurotransmission (such as NMDA-receptor agonists) that seem to be promising in difficult-to-improve symptoms as cognitive impairments and negative symptoms [112,113]
4.8.5. The need for future studies
Setrn and al found in there review of the literature about predictors of response to neuroleptic treatment in schizophrenia, that predictive models explained less then 80 % and more frequently less than 40 % of the outcome variance. These findings suggest that there are other factors influencing the prognosis of schizophrenia, which are still unknown [60], hence there is an important need for further studies in this area.
5. Conclusion
TRS remains a challenge for clinical practice and research. It is an undeniable and frequent clinic reality and a real public health problem. For research, having a wide consensus defining the boundaries of TRS is important for comparability and reliability of future studies. TRS is a heterogeneous entity, and has a multifactorial determinism. It is not, at least for some patients, a fatality, but rather the culmination of several risk factors, some of which seem to be accessible to effective therapeutic interventions. According to this opinion, TRS would be partly preventable and reversible.
Nomenclature
TRS : treatment-resistant schizophrenia;
SKZ: schizophrenia;
SAD: schizo-affective disorder;
NLP: neuroleptic;
CPZ: Chlorpromazine;
BPRS: Brief Psychiatric Rating Scale;
CGI: Clinical global impressions;
GAF: Global assessment of functioning;
SGA: Second generation antipsychotics;
FGA: first generation antipsychotics;
APA: American Psychiatric Association;
NICE: National institute for clinical excellence;
IPAP: The International Psychopharmacology Algorithm Project;
TMAP: The Texas Medication Algorithm Project
Acknowledgments
I offer my thanks to Karim Tabbane, Hatem Dammak and Mohamed Triki for their valuable assistance in the elaboration of this work. There were no funding sources for this work.
References
- 1.
Management of treatment resistance in schizophrenia. Biological PsychiatryConley R. R Kelly D. L 2001 Dec 1;50 11 898 911 - 2.
A selective review of recent North American long-term followup studies of schizophrénia. Schizophr BullMcglashan T. H 1988 14 4 515 42 - 3.
Cost-effectiveness of clozapine for treatment resistant schizophrenic patients. Hosp Community PsychiatryRevicki D. A Luce B. R Weschler J. M Brown R. E Adler M. A 1990 Aug;41 8 850 4 - 4.
Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry.Kane J Honigfeld G Singer J Meltzer H 1988 Sep;45 9 789 96 - 5.
eds. Treatment Resistance in Schizophrenia. Braunschweig, Germany: Vieweg Verlag;Dencker S. J Kulhanet F 1988 - 6.
Defining treatment refractoriness in schizophrenia. Schizophr BullBrenner H. D Dencker S. J Goldstein M. J et al 1990 16 4 551 61 - 7.
The evolving definition of treatment resistance. J Clin PsychiatryPeuskens J 1999 Suppl12 4 8 - 8.
Effects of stringent criteria on eligibility for clozapine among public mental health clients. Psychiatr Serv.Juarez-reyes M. G Shumway M Battle C Bacchetti P Hansen M. S Hargreaves W. A 1995 Aug;46 8 801 806 - 9.
Estimating clozapine’s cost to the nation. Hosp Community PsychiatryTerkelsen K. G Grosser R. C 1990 Aug;41 8 863 869 - 10.
Notion de schizophrénie résistante. L’EncéphaleVanelle J. M 1995 NS3) 13-21. - 11.
Clozapine eligibility among state hospital patients. Schizophr Bull.Essock S. M Hargreaves W. A Dohm F. A Goethe J Carver L Hipshman L 1996 22 1 15 25 - 12.
Concept and Management of Treatment Resistant Schizophrenia (TRS). Indian J Psychiatry.Painuly N Gupta N Avasthi A 2004 Apr-Jun;46 2 125 134 - 13.
Pharmacological treatment strategies in the non respensive schizophrenic patient. Int Clin PsychopharmacolBarnes T. R Mcevedy C. J 1996 Suppl 2): 67-71. - 14.
randomized study comparing the efficacy and safety of sertindole and risperidone in patients with treatment-resistant schizophrenia. J. Clin. PsychiatryKane J. M Potkin S. G Daniel D. G Buckley P. F A Double-blind 2011 72 194 204 - 15.
MOZART Study Group, Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study. Schizophr. Res.Sacchetti E Galluzzo A Valsecchi P Romeo F Gorini B Warrington L 2009 113 112 121 - 16.
Olanzapine HGCK Study Group,. Olanzapine versus clozapine in treatment-resistant or treatmentintolerant schizophrenia. Prog. Neuropsychopharmacol. Biol. PsychiatryBitter I Dossenbach M. R Brook S Feldman P. D Metcalfe S Gagiano C. A Füredi J Bartko G Janka Z Banki C. M Kovacs G Breier A 2004 28 173 180 - 17.
Clinical predictors of therapeutic response to clozapine in a sample of Turkish patients with treatment-resistant schizophrenia. Prog. Neuropsychopharmacol. Biol. PsychiatrySemiz U. B Cetin M Basoglu C Ebrinc S Uzun O Herken H Balibey H Algul A Ates A 2007 31 1330 1336 - 18.
National Institute for Clinical Excellence Technology appraisal Guidance43 Guidance on the use of newer (atypical) antipsychotic drugs for the treatment of schizophrenia. London: NICE,2002 - 19.
Dell’Osso, L., Bandettini di Poggio, A., Carmassi, C., Cecconi, D., Fenzi, M., Chiavacci, M.C., Bottai, M., Ramacciotti, C.E., Cassano, G.B. Clozapine in treatment-resistant patients with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder: a naturalistic 48-month follow-up study. J. Clin. PsychiatryCiapparelli A 2003 64 451 458 - 20.
Olanzapine in refractory schizophrenia after failure of typical or atypical antipsychotic treatment: an open-label switch study. J. Clin. Psychiatry.Lindenmayer J. P Czobor P Volavka J Lieberman J. A Citrome L Sheitman B Chakos M Mcevoy J. P 2002 63 931 935 - 21.
Standardized remission criteria in schizophrenia. Acta Psychiatr Scand.Van Os J Burns T Cavallaro R Leucht S Peuskens J Helldin L Bernardo M Arango C Fleischhacker W Lachaux B Kane J. M 2006 Feb;113 2 91 5 - 22.
Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry.Andreasen N. C 2005 Mar;162 3 441 9 - 23.
Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and Clozapine: Relation to extrapyramidal side effects. Archives of General Psychiatry,Farde L Nordstrom A. L Wiessel F. A et al 1992 49 538 544 - 24.
Treatment of neuroleptic resistant schizophrenia relapse. Psychopharmacology BulletinKinon B. J Kane J. M John C 1993 29 309 314 - 25.
A controlled dose comparison of haloperidol in newly admitted schizophrenic patients. Archives of General PsychiatryVan Putten T Marder S. R Mintz J 1990 47 754 758 - 26.
Conventional antipsychotic medications for schizophrenia. Schizophr Bull.Dixon L. B Lehman A. F Levine J 1995 21 567 577 - 27.
Poor neuroleptic response in acutely exacerbated schizophrenic patients. Acta Psychiatr Scand.Shalev A Hermesh H Rothberg J Munitz H 1993 87 86 91 - 28.
Kreyenbuhl J; American Psychiatric Association; Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry.Lehman A. F Lieberman J. A Dixon L. B Mcglashan T. H Miller A. L Perkins D. O 2004 Feb;161(2 Suppl):1 56 - 29.
http://www ipap.org/algorithms.php - 30.
The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry.Moore T. A Buchanan R. W Buckley P. F Chiles J. A Conley R. R Crismon M. L Essock S. M Finnerty M Marder S. R Miller D. D Mcevoy J. P Robinson D. G Schooler N. R Shon S. P Stroup T. S Miller A. L 2007 Nov;68 11 1751 62 - 31.
Treatment resistant schizophrenia and response to antipsychotics: a review. Schizophr Res.Suzuki T Remington G Mulsant B. H Rajji T. K Uchida H Graff-guerrero A Mamo D. C 2011 Dec;133(1-3):54-62. Epub 2011 Oct 14. - 32.
Defining treatment refractoriness in schizophrenia. Schizophr Bull.Brenner H. D Dencker S. J Goldstein M. J Hubbard J. W Keegan D. L Kruger G Kulhanek F Liberman R. P Malm U Midha K. K 1990 16 4 551 61 - 33.
Management of schizophrenia: an update. Indian Journal of PsychiatryKulhara P 1998 40 120 134 - 34.
Evaluation of treatment-resistant schizophrenia. Schizophr Bull.Conley R. R Buchanan R. W 1997 23 4 663 74 - 35.
Treatment refractory schizophrenia. Psychiatr Q.Lindenmayer J. P 2000 71 373 384 - 36.
Management of treatment-resistant patients with schozphrenia. Journal of Clinical PsychiatryMarder S. R 1996 Suppl 11): 26-30. - 37.
Standards of care and clinical algorithms for treating schizophrenia. Psychiatr Clin North AmSmith T. E Docherty J. P 1998 21 203 20 - 38.
http://www mass.gov/eohhs/docs/dmh/publications/schizophrenia-guidelines-full.pdf - 39.
Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 2nd ed. Cambridge University Press, New York, N.Y.,Stephen M Stahl M. D Ph D 2000 pages. - 40.
Sex differences in schizophrenia, a review of the literature. Acta Psychiatr ScandLeung A Chue P 2000 101 3 38 - 41.
Gender differences in onset of illness, treatment response, course and biologic indexes in first-episode schizophrenic patients. Am J PsychiatrySzymanski S Lieberman J. A Alvir J. M Mayerhoff D Loebel A Geisler S et al 1995 152 5 698 703 - 42.
Estrogen potentiation of phenothiazine-induced prolactin secretion in man. J Clin Endocrinol MetabolBuckman M. T Peake G. T 1973 37 6 977 980 - 43.
De Lisi LE: The significance of age of onset for schizophrenia Schizophr Bull1992 18 209 215 - 44.
Age at Onset and Gender of Schizophrenic Patients in Relation to Neuroleptic Resistance. Am J PsychiatryMeltzer H. Y Rabinowitz J Lee M. A Cola P. A Ranjan R Findling R. L Thompson P. A 1997 Apr;154 4 475 482 - 45.
Frith CD: The spectrum of structural brain changes in schizophrenia: age of onset as a predictor of cognitive and clinical impairments and their cerebral correlates. Psychol MedJohnstone E. C Owens D. G Bydder G. M Colter N Crow T. J 1989 19 91 103 - 46.
[46]. Mandelbrote BM: Schizophrenia with good and poor outcome, I: early clinical features, response to neuroleptics and signs of organic dysfunction. Br J PsychiatryKolakowska T Williams A. O Ardern M Reveley M. A Jambor K Gelder M. G 1985 146 229 239 - 47.
Murray RM: Response to drugs in schizophrenia: the influence of family history, obstetric complications and ventricular enlargement. Psychol MedNimgaonkar V. L Wesseley S Tune L. E 1988 18 583 592 - 48.
Wooff K: Long-term course of hospitalization for schizophrenia, part I: risk for rehospitalization. Schizophr BullEaton W. W Mortensen P. B Herrman H Freeman H Bilker W Burgess P 1992 18 217 228 - 49.
Alvir JMJ, Mayerhoff DI, Geisler SH, Szymanski SR: Duration of psychosis and outcome in first-episode schizophrenia. Am J PsychiatryLoebel A. D Lieberman J. A 1992 149 1183 1188 - 50.
Gender differences in schizophrenia: hormonal effect or subtypes? Schizophr Bull.Castle D. J Abel K Takei N Murray R. M 1995 21 1 1 12 - 51.
Mcdonell M Mcclellan J 2007 Early-onset schizophrenia. In E. Mash & R. Barkley (Eds.), Assessment of childhood disorders (4th ed.,526 550 New York: Guilford Press. - 52.
Thalamus size and outcome in schizophrenia. Schizophrenia ResearchBrickman A. M Buchsbaum M. S Shihabuddin L Byne W Newmark R. E Brand J et al 2004 71 473 484 - 53.
Schizophrenic syndromes associated with treatment response. Prog Neuro Psychopharmacol & Biol Psychiat.Cuesta M. J Peralta V De Leon J 1994 18 87 99 - 54.
Social disability in schizophrenia: its development and prediction over 15 years in incidence cohorts in six European centres. Psychol Med.Wiersma D Wanderling J Dragomirecka E et al 2000 30 1155 1167 - 55.
Nonresponders to neuroleptics: a distinct subtype. In: Tamminga CA, ed. Schizoprenia Scientific Progress. Oxford, UK: Oxford University Press;Schulz S. C Conley R. R Kahn E. M et al 1989 1989 341 350 - 56.
Depressed mood and its functional correlates in institutionalized schizophrenia patients. Schizophrenia ResearchRieckmann N Reichenberg A Bowie C. R Parrella M White L Friedman J. I et al 2005 77 179 187 - 57.
Depression in Kraepelinian schizophrenia. Comprehensive PsychiatryKilzieh N Wood A. E Erdmann J Raskind M Tapp A 2003 44 1 6 - 58.
Clinical characteristics and risk factors for Kraepelinian subtypeof schizophrenia: Replication of previous findings and relation to summer birth. Psychiatry ResearchBralet M. C Loas G Yon V Marechal V 2002 111 147 154 - 59.
Schizophrenic patients with polydypsia and water intoxication more often have a form of schizophrenia first described by Kraepelin. Psychiatry Res. 2007 Aug 30;152(2-3):267-71. EpubBralet M. C Ton T Falissard B 2007 Apr 18. - 60.
Predictors of response to neuroleptic treatment in schizophrenia. Psychiatric Clinics Of North America. JuneStern R. G Kahn R. S Davidson M 1993 16 2 313 338 - 61.
Predictors of response to cognitive behavior therapy in the treatment of schizophrenia: a comparison of brief and standard interventions. Cognit Ther Res.Naeem F Kingdon D Turkington D 2008 32 651 656 - 62.
A randomised controlled trial of intensive cognitive behaviour therapy for chronic schizophrenia. Br Med J.Tarrier N Yusupoff L Kinney C et al 1998 317 303 307 - 63.
Baseline personality functioning correlates with 6 month outcome in schizophrenia. European PsychiatryFassino S Pierò A Mongelli E Caviglia M. L Delsedime N Busso F et al 2003 18 93 100 - 64.
Relation of familial schizophrenia to negative symptoms but not to the deficit syndrome. Am J PsychiatryMalaspina D Goetz R. R Yale S et al 2000 157 994 1003 - 65.
Expressed emotion and psychiatric relapse: A meta-analysis. Arch Gen Psychiatry.Butzlaff R. L Hooley J. M 1998 55 547 52 - 66.
Obstetric complications predict treatment response in first-episode schizophrenia. Psychol Med.Alvir J. M Woerner M. G Gunduz H Degreef G Lieberman J. A 1999 29 621 627 - 67.
Multiple admissions to an urban psychiatric center: a comparative study. Hosp Community Psychiatry.Carpenter M. D Mulligan J. C Bader I. A Meinzer A. E 1985 36 1305 1308 - 68.
Relapse in schizophrenia: is there a relationship to substance abuse? Schizophr Res.Gupta S Hendricks S Kenkel A. M Bhatia S. C Haffke E. A 1996 20 153 156 - 69.
Identifying modifiable risk factors for rehospitalization: a case-control study of seriously mentally ill persons in Mississippi. Am J Psychiatry.Sullivan G Wells K. B Morgenstern H Leake B 1995 152 1749 1756 - 70.
Substance abuse as a risk factor for tardive dyskinesia: a retrospective analysis of 1027 patients. Psychopharmacol Bull.Bailey L. G Maxwell S Brandabur M. M 1997 33 177 181 - 71.
Longitudinal studies of cognition and functional outcome in schizophrenia: implications for MATRICS.Schizophr Res.Green M. F Kern R. S Heaton R. K 2004 Dec 15;72 1 41 51 - 72.
What are the functional consequences of neurocognitive deficits in schizophrenia? American Journal of PsychiatryGreen M. F 1996 153 321 330 - 73.
Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the bright stuffQ? Schizophrenia BulletinGreen M. F Kern R. S Braff D. L Mintz J 2000 26 119 - 74.
Cognitive deficits as treatment targets in schizophrenia. Schizophrenia Research.Gold J. M 2004 72 21 28 - 75.
The Relationship of Structural Brain Imaging Parameters to Antipsychotic Treatment Response: A Review. J Psychiatr Neurosci,Friedman L Lys C Schulz S. C 17 2 1992 - 76.
Hulshoff Pol HE, Schnack HG, van Haren NEM, Seifert N, Kahn RS. Structural brain abnormalities in chronic schizophrenia at the extremes of the outcome spectrum. American Journal of PsychiatryStaal W. G 2001 158 1140 1142 - 77.
Very poor outcome schizophrenia: clinical and neuroimaging aspects. Int Rev Psychiatry.Mitelman S. A Buchsbaum M. S 2007 Aug;19 4 345 57 - 78.
Ventricular enlargement in poor-outcome schizophrenia. Biological PsychiatryDavis K. L Buchsbaum M. S Shihabuddin L Spiegel-cohen J Metzger M Frecska E et al 1998 43 783 793 - 79.
Progressive structural brain abnormalities and their significance on outcome: A longitudinal MRI study early in the course of schizophrenia. Archives of General PsychiatryHo B. C Andreasen N. C Nopoulos P Magnotta V Arndt S Flaum M 2003 60 585 594 - 80.
Longitudinal study of brain morphology in first episode schizophrenia. Biological PsychiatryLieberman J. A Chakos M. H Wu H Alvir J. M Hoffman E Robinson D et al 2001 49 487 499 - 81.
Caudate and putamen volumes in good and poor outcome patients with schizophrenia. Schizophrenia ResearchBuchsbaum M. S Shihabuddin L Brickman A. M Miozzo R Prikryl R Shaw R et al 2003 64 53 62 - 82.
Hulshoff Pol HE, Lems EB, van Haren NE, Schnack HG, van der Linden JA, Schothorst PF, van Engeland H, Kahn RS. Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry.Cahn W 2002 Nov;59 11 1002 10 - 83.
Lindenmayer J-P et al. Effect of a Haloperidol Challenge on Regional Brain Metabolism in Neuroleptic-Responsive and Nonresponsive Schizophrenic Patients. Am J PsychiatryBartlett E J Brodie J. D Simkowitz P Schlösser R Dewey S. L 1998 155 337 343 - 84.
Bunney WE Jr: Effects of clozapine and thiothixene on glucose metabolic rate in schizophrenia. NeuropsychopharmacologyBuchsbaum M. S Potkin S. G Marshall J. F Lottenberg S Teng C. Y Heh C. W Tafalla R Reynolds C Abel L Plon L 1992 6 155 164 - 85.
Siegel BV Jr, Lohr J, Katz M, Gott~schalk LA, Gulasekaram B, Marshall JF, Lottenberg S, Teng CY, Abel L, Plon L, Bunney WE Jr: Striatal metabolic rate and clinical response to neuroleptics in schizophrenia. Arch Gen PsychiatryBuchsbaum M. S Potkin S. G 1992 49 966 974 - 86.
Evans LEJ Beumont PJV, Luttrell B. Prolactin response as a guide to neuroleptic treatment of schizophrenia. Prog Reprod Biol1980 6 260 263 - 87.
Serum prolactin as a correlate of clinical response to haloperidol. J Clin PsychopharmacolVan Putten T Marder S. R Mintz J 1991 11 6 357 361 - 88.
Watern aux C, Pappalardo KM, Fitzgibbon ME et al. Haloperidol response and plasma catecholamines and their metabolites. Schizophr ResGreen A. I Alam M. Y Boshes R. A 1993 10 1 33 37 - 89.
Homovanillic acid in the cerebrospinal fluid: patterns of response after four weeks of neuroleptic treatment. Biol PsychiatrySharma R. P Javaid J. I Janicak P. G Davis J. M Faull K 1993 34 3 128 134 - 90.
Plasma homovanillic acid levels and therapeutic outcome in schizophrenics: comparisons of neuroleptic-naive first-episode patients and patients with disease exacerbation due to neuroleptic discontinuance. Biol PsychiatryAkiama K Tsuchid A K Kanzaki A Ujike H Hamamura T Kondo K et al 1995 38 1 639 648 - 91.
Plasma prolactin and plasma homovanillic acid: predictors of clinical response in schizophrenia. Biol PsychiatryDavila R Gonzalez M. A Zumarra M Andia I Guimon J Silva R. R et al 1995 38 267 269 - 92.
Plasma homovanillic acid and treatment response in a large group of schizophrenic patients. Schizophr ResChang W. H Hwu H. G Chen T. Y Lin S. K Lung F. W Chen H et al 1993 10 3 259 265 - 93.
d-Amphetamine-induced heterogeneous changes in psychotic behavior in schizophrenia. Am J PsychiatryVan Kammen D. P et al 1982 139 991 997 - 94.
Growth hormone and prolactin response to apomorphine in schizophrenia and the major affective disorders. Arch Gen PsychiatryMeltzer H. Y et al 1984 41 512 519 - 95.
Mismatch negativity deficits are associated with poor functioning in schizophrenia patients. Arch Gen Psychiatry.Light G. A Braff D. L 2005 62 127 136 - 96.
What does electrodermal activity tell us about prognosis in the schizophrenia spectrum? Schizophr Res.Dawson M. E Schell A. M 2002 Mar 1;54(1-2):87-93. - 97.
Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry.Perkins D. O Gu H Boteva K Lieberman J. A 2005 Oct;162 10 1785 804 - 98.
The natural history and pathophysiology of treatment resistant schizophrenia. J Psychiatr Res.Sheitman B. B Lieberman J. A 1998 May-Aug;32(3-4):143-50. - 99.
Neuroprotection: a new strategy in the treatment of schizophrenia. Neurobiological basis of neurodegeneration and neuroprotection. CNS Spectr.Lieberman J. A 2007 Oct;12(10 Suppl 18):4-6. - 100.
Sheitman B at al. Psychobiologic correlates of treatment response in schizophrenia. NeuropsychopharmacologyLieberman J. A Alvir M. A Koreen A Geisler S Chacos M 1996 S-21S. - 101.
Factors influencing treatment response an doutcome of first-episode schizohrenia: implications for understanding the pathophysiology of schizophrenia. J Clin PsychiatryLieberman J. A Koreen A. R Chakos M et al 1996 suppl 9): 5-9. - 102.
Alvir JMJ, Geisler S, Koreen A, Sheitman B et al. P redictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. Am J PsychiatryRobinson D. G Woerner M. G 1999 156 544 549 - 103.
Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry.Andreasen N. C 2005 Mar;162 3 441 9 - 104.
Standardized remission criteria in schizophrenia. Acta Psychiatr Scand.Van Os J Burns T Cavallaro R Leucht S Peuskens J Helldin L Bernardo M Arango C Fleischhacker W Lachaux B Kane J. M 2006 Feb;113 2 91 5 - 105.
Keefe RSE Frescka E, Apter SH, Davidson M, Macaluso JM, Hirschowitz J, et al. Clinical characteristics of Kraepelinian schizophrenia: Replication and extension of previous findings. American Journal of Psychiatry1996 153 806 811 - 106.
Subtyping schizophrenia according to outcome or severity: A search for homogeneous subgroups. Schizophrenia BulletinRoy M. A Merette C Maziade M 2001 27 115 138 - 107.
Reducing the duration of untreated first episode psychosis. Effect on clinical presentation. Arch Gen Psychiatry.Melle I Larsen T. K Haahr U Friis S Johannessen J. O Opjordsmoen S et al 2004 61 143 150 - 108.
Randomized controlled trial of interventions designed to reduce the risk of progression to first episode psychosis in a clinical sample with suthreshold symptoms. Arch Gen Psychiatry.Mcgorry P. D Yung A. R Phillips L. J Yuen H. P Francey S Cosgrave E. M et al 2002 59 921 928 - 109.
DahlstrÖm M, Larmo I, Räsänen P,Juriloo A. Antipsychotic drug treatment in the prodromal phase of schizophrenia. Am J PsychiatryCannon T. D Huttunen M. O 2002 159 1230 1232 - 110.
Cognitive remediation and cognitive assistive technologies in schizophrenia. Encephale.Sablier J Stip E Franck N 2009 Apr;35 2 160 7 - 111.
Functional neuroimaging and electrophysiology biomarkers for clinical trials for cognition in schizophrenia. Schizophr BullCho R. Y Ford J. M Krystal J. H Laruelle M Cuthbert B Carter C. S 2005 31 4 865 869 - 112.
Integrated treatment of schizophrenia. Psychiatr Serv.Lenroot R Bustillo J. R Lauriello J Keith S. J 2003 Nov;54 11 1499 507 - 113.
Coyle JT: The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. American Journal of PsychiatryGoff D. C 2001 158 1367 1377 - 114.
Predictive values of neurocognition and negative symptomes on functional outcome in schizophrenia: A longitudinal first-episode study with 7 year follow-up. Am J PsychiatryMilev P Ho B-C Andreasen N 2005 162 495 506