Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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Effects of antipsychotic drugs on insight in schizophrenia Oriana Bianchini a,b,n,1, Stefano Porcelli a,1, Claudia Nespeca a, Dario Cannavò b, Angela Trappoli a, Eugenio Aguglia b, Diana De Ronchi a, Alessandro Serretti a a b
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123 Bologna, Italy Institute of Psychiatry, University of Catania, Via Santa Sofia 78, 95123 Catania, Italy
art ic l e i nf o
a b s t r a c t
Article history: Received 2 February 2013 Received in revised form 16 March 2014 Accepted 20 March 2014
Lack of insight is predominant in schizophrenia though the causes are still unclear. The present study was carried on to investigate the effect of three Second Generation Antipsychotics (SGAs) and Haloperidol on insight and the associations among different clusters of symptoms and insight. Fiftyfive patients have been recruited at the moment of pharmacological switch needed for psychotic exacerbation, from other antipsychotic drugs to Olanzapine, Aripiprazole, Ziprasidone and Haloperidol. Patients have been followed for 6 months and evaluated at baseline, after 3 months and after 6 months. Regarding the insight improvement, all SGAs resulted more effective than Haloperidol, while no difference was detected among different SGAs. Concerning psychopathology, all SGAs showed a better efficacy than Haloperidol, positive symptoms apart. All SGAs showed a similar efficacy on all domains, except for negative symptoms which resulted less responsive to ziprasidone and haloperidol. An association between improvement of insight and psychopathology was detected. Furthermore, insight appears to be related to psychopathology severity, particularly to negative symptoms. However, the observed different effectiveness of Ziprasidone on negative symptoms and insight suggests that these psychopathological features may be not strictly related and, thus, they may be sustained by different psychopathological processes. & 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Schizophrenia Insight Antipsychotic Psychopathology
1. Introduction According to recent epidemiological data, schizophrenia has a lifetime prevalence of 4.0/1000 individuals worldwide (Saha et al., 2005); moreover, it represents the eighth cause of disability among young people with an important economic burden for the society (Serretti et al., 2009). The disease is characterized by frequent acute relapses, which are due to several causes. Among them, one of the most relevant is the lack of treatment compliance. Poor treatment compliance could be due to several reasons, such as lower tolerability of treatment, complexity of the medication schedule, comorbidity with alcohol consumption, demographical factors (e.g. poor social support), poor relationship with the therapist or presence of delusion of persecution, poisoning or grandeur. However, several studies showed that impaired insight represents one of the main risk factor for lack of treatment compliance (Emsley et al., 2008; Acosta et al., 2012). Consistently, it has been reported that a good insight was one of the main predictor of both a better pharmacological compliance and a better general outcome (Amador and Gorman, 1998). Unfortunately, Corresponding author at: Department of Psichiatry, University of Catania,Via Santa Sofia 78, Catania, Italy. Tel.: þ 39 0953782470; Mobile:+39 3922824098. E-mail address: [email protected] (O. Bianchini). 1 These authors contributed equally to this work.
the lack of insight is predominant among schizophrenic patients compared to other psychiatric patients (Pini et al., 2001), with a prevalence of about 56–67% of poor insight patients (Bayard et al., 2009). With the term insight we referred to a phenomenological construct, which was described for the first time in 1836 in “Lehrbuch der Psichiatrie”, a text by Krafft-Ebingis. In this text the “einsichtslos” (i.e. insight) was considered as the inability of the patient to recognize his delusional aspects (Amador and Gorman, 1998). However, the original definition of insight was enriched later with other aspects. Particularly, nowadays, multidimensional accounts of insight have been accepted within research (Konstantakopoulos et al., 2013). David (1990) proposed three distinct but partially overlapping dimensions of insight, namely the ability to recognize that one has a mental illness, compliance with treatment, and the capacity to relabel unusual mental events (e.g. delusions and hallucinations) as pathological. Other authors suggested that two major components of insight are the capacity of patient in recognizing the pathological nature of symptoms (Amador et al., 1993) or the awareness of the benefits of taking the medication (Amador et al., 1993). Thus, the concept of insight does not include only the awareness of illness, but also the capacity in examining the different levels of motivation and the acceptance of a new point of view that
http://dx.doi.org/10.1016/j.psychres.2014.03.022 0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Bianchini, O., et al., Effects of antipsychotic drugs on insight in schizophrenia. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.03.022i
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could undermine their beliefs (Aguglia et al., 2002). For this reason, the modern scales developed to measure patient's insight are composed by different parts, which investigate all these aspects. Among these scales, the most used nowadays are the Schedule for the Assessment of Insight developed by David et al. (1992) and the Scale to Assess Unawareness of Mental Disorder developed by Amador and Strauss (1990). In the last years insight has been investigated in relationship with the severity of psychopathology (Hayashi et al., 1999), the acceptance of therapy (Misdrahi et al., 2012) and the cognitive impairment (Markova and Berrios, 1995). Despite some studies investigated these issues, no definitive conclusion has been drawn so far. Particularly, the relationship between insight and psychopathology is still not clear. As a matter of fact, a meta-analysis performed by Mintz et al. showed a weak association among insight and both positive and negative symptoms (Mintz et al., 2003). Unfortunately, few studies investigated the relationship between insight and global psychopathology severity, while a lot of studies investigated the association among insight and different psychopathological clusters, such as positive and negative symptomatological clusters. Particularly, some authors found that insight was inversely related to positive symptoms, while no association was found concerning the others cluster of symptoms (e.g. negative symptoms) (Kim et al., 1997; McEvoy et al., 1989). Interestingly, the study by McEvoy et al. suggested that the relationship between insight and positive symptoms varied according to the disease phase. Indeed, a relative strong correlation was found during the acute phase of the disease, while this relationship became weaker during the maintenance phase. This observation could be due to the impact of severe psychotic symptoms on the global cognition of the patient, which is related to insight as well. Consistently, from an etiological point of view, it is hard to link positive symptoms directly to insight. Indeed, the more accepted hypothesis posits that lack of insight in schizophrenic patient is due to a prefrontal impairment, which is accountable also for both the negative and cognitive symptoms (Varga et al., 2007). Nonetheless, studies which investigated the association between insight and negative symptoms did not find any correlation (Simon et al., 2009). On the other hand, some studies suggested a possible association between cognitive function impairment and poor insight (Mohamed et al., 1999), suggesting that poor insight may be mainly due to the cognitive impairment of the patient. This finding is consistent with a recent study by Wiffen et al. (2012), which suggests a strong relationship among neuropsychological deficits and poor insight. Interestingly, authors hypothesized a learning component of insight, which may be enhanced through appropriate psychological and rehabilitative treatments. Nonetheless, overall the relationship between insight and the psychopathological status has not been deeply investigated so far and further studies are required to draw definitive conclusion. Furthermore, to the best of our knowledge, very few studies were specifically carried out to investigate the effects of different antipsychotic drugs on insight. Despite some limitations in the design and quality of the existing studies on the comparative effectiveness of First Generation Antipsychotics (FGAs) and Second Generation Antipsychotics (SGAs) (e.g. most frequent comparison of SGAs only with haloperidol, heterogeneity in clinical features and population data, etc.), the latter have been proved to be more effective in improving negative symptoms (Hartling et al., 2012). On the other hand, the superiority of SGAs on FGAs on cognitive symptoms is still controversial (McKenna and Mortimer, 2014). Taking into account these data, it could be hypothesized that SGAs may have a specific effect on insight as well. Consistently, one preliminary study by Aguglia et al. showed that SGAs improved patients' insight more than FGAs (Aguglia et al., 2002). Nonetheless, the sample size of
this previous study was small and it did not allow to draw consistent conclusions as well as to compare the effects of different SGAs. However, the detection of a specific effect on this fundamental psychopathological aspect by a specific antipsychotic drug may allow to better understand the biological origin of insight and its relationship with other symptoms, also in providing important clinical information. Taking into account all these considerations, the present study was carried out to investigate the specific effect of three SGAs (aripiprazole, olanzapine, ziprasidone) and one FGA (haloperidol) on insight in a sample of schizophrenic patients, which needed a pharmacological switch for psychosis exacerbation. As secondary aims, we investigated the associations among different clusters of symptoms and insight, also considered in its distinct components, in order to provide further evidences for previous literature data.
2. Methods We included in the study 55 patients recruited at the Department of Psychiatry of University Hospital of Catania, Sicily, Italy. The diagnosis was made by two different M.D. according to the DSM-IV TR criteria. The duration of study was 6 months and there were three times of follow up: at baseline (T0), at 3 months (T1) and at 6 months (T2). All recruited patients needed a pharmacological switch for psychosis exacerbation at the inclusion in the study. All patients (18–65 years old) provided written informed consent before participating in the study. The study was carried out in accordance with the latest version of the Declaration of Helsinki. At the recruitment, patients were assigned randomly to one of the antipsychotic included in the present study. The drugs used were chosen because (1) haloperidol (HAL) is the most used FGA in our country and worldwide; (2) olanzapine (OLA) is one of the SGA with more proven efficacy (Glick et al., 2011); (3) aripiprazole (ARI) is one of the SGA that seems to have a greater effectiveness on both negative and cognitive symptoms in comparison to other SGAs (Stip and Tourjman, 2010) and (4) ziprasidone (ZIP) is one of the newest SGAs in our country and its effect on specific psychopathological features has not been deeply investigated so far (Montes, 2012). Fifteen patients were switched to OLA, 15 to HAL, 15 to ARI and 10 to ZIP. The switch was made gradually. The range of dosage of antipsychotics was 10–20 mg for OLA, 2–9 mg for HAL, 10–30 mg for ARI and 80–160 mg for ZIP. The psychopathological status of patients was measured at each visit through the administration of the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1989), by a trained rater, who was blinded to the patients' treatment. Levels of insight were assessed by the same rater through the administration of the Schedule for the Assessment of Insight (SAI) (David et al., 1992), a semi-structured interview that measures three different dimensions of insight: therapy compliance (SAI 1), awareness of illness (SAI 2) and identification of psychotic symptoms (SAI 3). The improvement at PANSS scale was calculated with the formula [(PANSS T030) (PANSS T2-30)/(PANSS T0-30)] and the improvement at SAI scale with the formula [(SAI T0) (SAIT2)/(SAIT0)]. The improvement of each PANSS and SAI subscales (respectively positive, negative and general subscales and SAI1, SAI2 and SAI3) was calculated and considered for the analyses. All data analyses were performed using the Statistica package, version 7.0 (StatSoft Italia, Vigonza, Padua, Italy) for Windowss (1995). Analysis of variance (ANOVA), analysis of co-variance (ANCOVA) and chi-square statistical analyses were performed when appropriate. All p-values were 2-tailed. GPower (http://www.psycho.uni-duesseldorf.de/aap/ projects/gpower/) was employed for the power analysis. With these parameters (p ¼ 0.05) we had a sufficient power (0.80) to detect an effect size of 0.2, that corresponded to the possibility of detecting differences on PANSS total improvement scores of two points.
3. Results The characteristics of the sample are shown in Table 1. The groups of patients, separated by the antipsychotic drugs, were homogeneous for age, sex, PANSS and SAI scores at the baseline (Table 1). Regarding insight, analyses showed that patients of the HAL group showed a lower improvement compared to SGAs patients (overall p o0.001, HAL vs OLA p o0.001, HAL vs ARI p o0.001, HAL vs ZIP p o0.001) (Fig. 1). Among the SGAs, no difference was detected in improving insight. When we controlled for possible confounding factors, we found that a higher psychopathology at the baseline predicts a higher improvement in insight (PANSS
Please cite this article as: Bianchini, O., et al., Effects of antipsychotic drugs on insight in schizophrenia. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.03.022i
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Table 1 Demographic characteristics and general analysis of the sample. Groups
Patients
Sex M (%)
Age
Doses mg/day
PANSS BSL
PANSS IMPR.%a
SAI BSL
SAI IMPR.%a
Total OLA HAL ARI ZIP
55 15 15 15 10
35 (63.6%) 10 (66.67%) 10 (66.67%) 7(46.67%) 8 (80%)
39.1 7 11 38 7 11.2 39.9 7 11.9 38.2 7 10.6 40.9 7 11.3
10–20 2–9 10–30 80–160
120.2 7 20.9 126.6 7 22.3 112.5 7 19.3 122.4 7 19.3 118.8 7 22.7
267 17 257 1 177 11 307 16 377 25
4.8 7 2.6 4.17 3.3 5.2 7 2.0 4.4 7 2.6 5.8 7 2.0
337 33 447 36 47 20 457 33 417 15
PANSS and SAI improvement percentage7S.D.
Total p o0.001, F¼ 13.54; PANSS Positive p o0.001, F¼ 13.31; PANSS Negative p o0.001, F¼14; PANSS General has no effects). Interestingly, when we controlled for psychopathological improvement, we found an effect only for improvement in negative symptomatology (p o0.001, F¼13.87). No effect of sex and age was found. Moreover, we investigated the possible relationship among each antipsychotic included in the study and the improvement of score obtained at each subscale of SAI. We found that all SGAs are more effective than HAL in improving score obtained at SAI 1 and SAI 2 (p o0.001), while no significant difference was found among them. On the other hand, no significant difference among SGAs and HAL was detected for SAI 3 (p 40.05). Regarding psychopathology, when we compared the HAL group with the SGAs group, we found a greater improvement at the PANSS total score in SGAs group (p ¼0.002). Among the SGAs investigated, no one showed a greater efficacy than the others. Interestingly, in the PANSS positive subscale, we did not find any difference between HAL and SGAs, as well as among the different SGAs investigated. On the other hand, SGAs showed overall greater efficacy in improving negative symptoms compared to HAL (p ¼0.01); particularly, OLA and ARI were more effective than HAL (respectively p ¼0.01 and p ¼0.02), while this difference was not detected comparing HAL with ZIP. Regarding the general symptomatology, we found a greater overall efficacy of SGAs on FGA (p o0.001), without any difference among the different SGAs. When we investigated the relationship between insight and psychopathology, we found an association between the improvement of insight and global psychopathology measured by PANSS (p¼0.02; R2 adj.¼0.08). Particularly, the improvement of insight was related to improvement both in negative (po0.001; R2 adj.¼ 0.19) and in general (p¼0.01; R2 adj.¼0.09) symptomatology, but not for the improvement of positive symptomatology. Particularly, we found that SAI 1 (therapy compliance) score was associated with global psychopathology (PANSS total score) and with positive symptomatology (PANSS positive subscale) (po0.001 and po0.05 respectively), while there was no association with negative and general PANSS subscales (p40.05). Regarding the score obtained at SAI 2 (awareness of illness), they were associated with PANSS total score and with the other PANSS subscales scores (po0.001 for all the results), negative subscale apart (p40.05). Finally, SAI 3 (identification of psychotic symptoms) scores were associated with PANSS positive and negative subscales scores (both po0.001), but not with the general subscale and the total PANSS scores (p40.05).
4. Discussion The aim of this study was to evaluate, in patients affected by schizophrenia, the effectiveness of different antipsychotics in improving insight and to investigate the relationship between psychopathology and insight improvements. Until now, few studies have been conducted to directly investigate the influence of pharmacological treatment on insight. Further, studies found in literature were often not specifically designated for
Insight and Drugs Current effect: F=5,3, p=,00008 13 12 11 10 9 8 SAI
a
7 6 5 4 3 2 1 T0
T1
T2
Olanzapine Haloperidol Aripiprazole Ziprasidone
Fig. 1. Insight improvement induced by the four AP drugs.
this aim and they have several methodological limitations (e.g. the use of non-validated scales in order to determine insight). Consistently, few literature data are available concerning specifically the efficacy of SGAs in improving insight in schizophrenia. In this background, our study revealed a greater improvement of the levels of insight, in a six-month period, in patients with schizophrenia treated with SGAs with respect to those treated with HAL. This finding is consistent with previous results (Aguglia et al., 2002; Rocca et al., 2008), although one previous study failed to find any differences among FGAs and SGAs as well (Sajatovic et al., 2002). However, these studies have several methodological limitations (such as small sample size, non-blinded, nonrandomized design, absence of direct comparison among different antipsychotics, etc.), which have to be considered in the interpretation of the results. Therefore, till now the suggested superiority of SGAs on FGAs in improving insight is still a matter of debate (Leucht et al., 2009; Lewis, 2009) and further specific investigation, with rigorous methodology, is needed to better dissect this issue. On the other hand, it is not completely clear how the SGAs could affect insight in schizophrenia. In our study we evaluated the effect of specific SGAs, investigating their impact in comparison with HAL, taking into account the different psychopathological dimensions of schizophrenia, which in turn could directly affect insight (e.g. negative symptomatology). All three SGAs were found to be more effective than HAL in improving the global symptoms at the PANSS. The trend of such improvement also reflects on insight, which improved significantly with all three SGAs compared to HAL; the three SGAs resulted in greater improvement of insight comparatively. Therefore, improvement of insight with SGAs could be, at least partially, due to the psychopathological improvement rather than a specific effect of these drugs on insight itself. In particular, when we compared the effectiveness of the four antipsychotics with the three distinct subscales of SAI, we found that SGAs are more effective than HAL on the component concerning the therapy compliance and the awareness of illness (SAI 1 and SAI 2 respectively), while no
Please cite this article as: Bianchini, O., et al., Effects of antipsychotic drugs on insight in schizophrenia. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.03.022i
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significant difference has been found concerning the identification of psychotic symptoms as well as non-physiological phenomena (SAI 3). This latter result might be consistent with the finding that, at the breakdown of the symptomatological dimensions at PANSS, significant differences among the various drugs did not emerge concerning the positive symptomatology. On the other hand, SGAs showed greater effects on both general and negative symptoms compared to HAL, although for ZIP the difference was not significant regarding negative symptoms. The lack of a relevant difference, in terms of efficacy, between FGAs and SGAs on positive symptoms found in our study, could suggest that this psychopathological dimension may not be related, at least in the post-acute phase of the disease, to improvement in insight. This finding is consistent with previous results (McEvoy et al., 1989). On the contrary, we found a higher efficacy of SGAs on negative symptoms and though only 19%, we also detected a positive association between improvement of such psychopathological dimension and improvement of insight. Negative symptoms of schizophrenia are widely suspected to reflect a frontal lobe dysfunction (Semkovska et al., 2001) and different studies associated with insight to poor cognitive performance and damage of the prefrontal cortex (Aleman et al., 2006). The hypothesis that SGAs have a positive impact on specific cognitive functions (Keefe et al., 1999; Woodward et al., 2005), could explain the better response of negative symptoms and the improvement of the insight levels observed in our study with these drugs. The higher efficacy of SGAs on negative symptoms could partially explain their effects on insight. Indeed, we detected differences among SGAs about the efficacy on negative symptoms (OLA and ARI resulted superior to ZIP) but not concerning the efficacy in improving insight, not even when we consider the three distinct dimensions detected by SAI. This finding is consistent with previous reports (Mintz et al., 2003), suggesting a possible independence between the two domains. Further, despite the significant association observed between psychopathology and insight, the association is far than complete and many aspects still need to be clarified. For example, insight may be related to other psychopathological domains, such as anxiety and depressive symptomatology, which are common symptoms in schizophrenia and they could be due to several factors (Ekinci et al., 2012). Therefore, other neurobiological mechanisms of action of the SGAs may be involved in the observed insight improvement, likely involving specific brain regions related to insight. Such results sustain the hypothesis that insight could be considered a specific psychopathological dimension of schizophrenia, which is not entirely associated to other symptoms. To the best of our knowledge, this is the first study that investigated, beside the association between insight and other psychopathological domains, the impact of the single antipsychotic drugs on the insight levels. Furthermore, the study was designed specifically for this aim, as demonstrated by the use of SAI, which is a validated scale studied upon a large range of clinical samples. Unfortunately, the extended version of this scale, (SAI-E) (Kemp and David, 1997), which is more detailed, has not yet been available in Italian. Our study has several limitations, mainly the relatively small sample size. Furthermore, patients included in our sample had different duration of illness; clearly, the duration of illness also impacts the insight dimension (McEvoy et al., 2006), although the effect of this factor is still not clear (i.e. a longer disease may be related to a better insight as well as to the contrary, according to several other variables such as the relationship with the Psychiatric service, the response to treatment and so on). Unfortunately, data about the duration of illness were lacking; indeed all patients included needed a switch from another AP, but we did not collect data about duration of illness and thus we were not able to consider this relevant variable in the analyses. Lastly, the use of
the Scale to assess Unawareness of Mental Disorder (SUMD) (Amador and Strauss, 1990) in order to measure insight, being a scale with 74 items and largely approved as a multidimensional measuring system of insight, may have provided more information than SAI on specific components of insight. Additional studies with a larger sample and a randomized design are needed, in order to characterize the role and efficacy of antipsychotic drugs on the levels of insight in patients with schizophrenia. A clearer definition of the insight dimension within schizophrenia, including drug treatment that mostly affects insight, has also an important role in relation to the evidence of an association between insight and compliance, since a large percentage of patients with schizophrenia are not compliant to the drug treatment (Fenton et al., 1997; Lacro et al., 2002). In conclusion, this trial showed that SGAs seem to have a relevant impact on the improvement of the insight levels. Higher evidence could provide indications about what antipsychotic should be used in specific populations of patients with lack of insight. The mechanisms that indicate a better impact of the SGAs on the levels of insight could be manifold and derived from specific drug receptor profiles. Finally, considering the association between insight and cognitive symptoms, the development of new and targeted therapies to improve cognition in schizophrenia, might play an important role in improving insight as well. In this regard, a list of potential targets of cognitive-enhancing drugs has been promulgated by the MATRICS Consensus meeting, and it includes alfa7-nicotin receptor agonists, D1 receptor agonists, AMPA glutamatergic receptor agonists, alfa2-adrenergic receptor agonists, metabotropic glutamate receptor agonists glycine reuptake inhibitors, M1 receptor agonists and GABA A receptor subtype selective agonists (Green, 2007). Further research oriented in investigating specific associations among antipsychotics with different receptor's profiles, specific cognitive functions, psychopathology, time of treatment and insight, could provide important data on the brain regions implicated in these processes and on developing new and specific therapeutic interventions to improve insight at different stages of schizophrenia.
Role of funding source None.
Conflict of interest Prof. Serretti is or has been the consultant/speaker for: Abbott, Astra Zeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Pfizer, Sanofi, Servier. References Acosta, F.J., Hernandez, J.L., Pereira, J., Herrera, J., Rodriguez, C.J., 2012. Medication adherence in schizophrenia. World Journal of Psychiatry 2 (5), 74–82. Aguglia, E., De Vanna, M., Onor, M.L., Ferrara, D., 2002. Insight in persons with schizophrenia: effects of switching from conventional neuroleptics to atypical antipsychotics. Progress in Neuro-Psychopharmacology and Biological Psychiatry 26 (7–8), 1229–1233. Aleman, A., Agrawal, N., Morgan, K.D., David, A.S., 2006. Insight in psychosis and neuropsychological function: meta-analysis. British Journal of Psychiatry 189, 204–212. Amador, X.F., Gorman, J.M., 1998. Psychopathologic domains and insight in schizophrenia. Psychiatric Clinics of North America 21 (1), 27–42. Amador, X.F., Strauss, D.H., Yale, S.A., Flaum, M.M., Endicott, J., Gorman, J.M., 1993. Assessment of insight in psychosis. American Journal of Psychiatry 150 (6), 873–879.
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Markova, I.S., Berrios, G.E., 1995. Insight in clinical psychiatry revisited. Comprehensive Psychiatry 36 (5), 367–376. McEvoy, J.P., Apperson, L.J., Appelbaum, P.S., Ortlip, P., Brecosky, J., Hammill, K., Geller, J.L., Roth, L., 1989. Insight in schizophrenia. Its relationship to acute psychopathology. Journal of Nervous and Mental Disease 177 (1), 43–47. McEvoy, J.P., Johnson, J., Perkins, D., Lieberman, J.A., Hamer, R.M., Keefe, R.S., Tohen, M., Glick, I.D., Sharma, T., 2006. Insight in first-episode psychosis. Psychological Medicine 36 (10), 1385–1393. McKenna, J., Mortimer, Ann M., 2014. Current and future treatment modalities in schizophrenia: novel antipsychotic drugs and cognitive therapy. Expert Review of Neurotherapeutics 14 (1), 67–73. Mintz, A.R., Dobson, K.S., Romney, D.M., 2003. Insight in schizophrenia: a metaanalysis. Schizophrenia Research 61 (1), 75–88. Misdrahi, D., Petit, M., Blanc, O., Bayle, F., Llorca, P.M., 2012. The influence of therapeutic alliance and insight on medication adherence in schizophrenia. Nordic Journal of Psychiatry 66 (1), 49–54. Mohamed, S., Fleming, S., Penn, D.L., Spaulding, W., 1999. Insight in schizophrenia: its relationship to measures of executive functions. Journal of Nervous and Mental Disease 187 (9), 525–531. Montes, J.M., 2012. Use of ziprasidone in patients with schizophrenia in four European countries. European Psychiatry 26 (1 Suppl. 1), S29–S37. Pini, S., Cassano, G.B., Dell'Osso, L., Amador, X.F., 2001. Insight into illness in schizophrenia, schizoaffective disorder, and mood disorders with psychotic features. American Journal of Psychiatry 158 (1), 122–125. Rocca, P., Crivelli, B., Marino, F., Mongini, T., Portaleone, F., Bogetto, F., 2008. Correlations of attitudes toward antipsychotic drugs with insight and objective psychopathology in schizophrenia. Comprehensive Psychiatry 49 (2), 170–176. Saha, S., Chant, D., Welham, J., McGrath, J., 2005. A systematic review of the prevalence of schizophrenia. PLoS Medicine 2 (5), e141. Sajatovic, M., Rosch, D.S., Sivec, H.J., Sultana, D., Smith, D.A., Alamir, S., Buckley, P., Bingham, C.R., 2002. Insight into illness and attitudes toward medications among inpatients with schizophrenia. Psychiatric Services 53 (10), 1319–1321. Semkovska, M., Bedard, M.A., Stip, E., 2001. Hypofrontality and negative symptoms in schizophrenia: synthesis of anatomic and neuropsychological knowledge and ecological perspectives. L'Encéphale 27 (5), 405–415. Serretti, A., Mandelli, L., Bajo, E., Cevenini, N., Papili, P., Mori, E., Bigelli, M., Berardi, D., 2009. The socio-economical burden of schizophrenia: a simulation of costoffset of early intervention program in Italy. European Psychiatry 24 (1), 11–16. Simon, V., De Hert, M., Wampers, M., Peuskens, J., van Winkel, R., 2009. The relation between neurocognitive dysfunction and impaired insight in patients with schizophrenia. European Psychiatry 24 (4), 239–243. Stip, E., Tourjman, V., 2010. Aripiprazole in schizophrenia and schizoaffective disorder: a review. Clinical Therapeutics 32 (Suppl. 1), S3–S20. Varga, M., Magnusson, A., Flekkoy, K., David, A.S., Opjordsmoen, S., 2007. Clinical and neuropsychological correlates of insight in schizophrenia and bipolar I disorder: does diagnosis matter? Comprehensive Psychiatry 48 (6), 583–591. Wiffen, B.D., O'Connor, J.A., Russo, M., Lopez-Morinigo, J.D., Ferraro, L., Sideli, L., Handley, R., David, A.S., 2012. Are there specific neuropsychological deficits underlying poor insight in first episode psychosis? Schizophrenia Research 135 (1–3), 46–50. Woodward, N.D., Purdon, S.E., Meltzer, H.Y., Zald, D.H., 2005. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. International Journal of Neuropsychopharmacology 8 (3), 457–472.
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Effects of antipsychotic drugs on insight in schizophrenia Oriana Bianchini a,b,n,1, Stefano Porcelli a,1, Claudia Nespeca a, Dario Cannavò b, Angela Trappoli a, Eugenio Aguglia b, Diana De Ronchi a, Alessandro Serretti a a b
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123 Bologna, Italy Institute of Psychiatry, University of Catania, Via Santa Sofia 78, 95123 Catania, Italy
art ic l e i nf o
a b s t r a c t
Article history: Received 2 February 2013 Received in revised form 16 March 2014 Accepted 20 March 2014
Lack of insight is predominant in schizophrenia though the causes are still unclear. The present study was carried on to investigate the effect of three Second Generation Antipsychotics (SGAs) and Haloperidol on insight and the associations among different clusters of symptoms and insight. Fiftyfive patients have been recruited at the moment of pharmacological switch needed for psychotic exacerbation, from other antipsychotic drugs to Olanzapine, Aripiprazole, Ziprasidone and Haloperidol. Patients have been followed for 6 months and evaluated at baseline, after 3 months and after 6 months. Regarding the insight improvement, all SGAs resulted more effective than Haloperidol, while no difference was detected among different SGAs. Concerning psychopathology, all SGAs showed a better efficacy than Haloperidol, positive symptoms apart. All SGAs showed a similar efficacy on all domains, except for negative symptoms which resulted less responsive to ziprasidone and haloperidol. An association between improvement of insight and psychopathology was detected. Furthermore, insight appears to be related to psychopathology severity, particularly to negative symptoms. However, the observed different effectiveness of Ziprasidone on negative symptoms and insight suggests that these psychopathological features may be not strictly related and, thus, they may be sustained by different psychopathological processes. & 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Schizophrenia Insight Antipsychotic Psychopathology
1. Introduction According to recent epidemiological data, schizophrenia has a lifetime prevalence of 4.0/1000 individuals worldwide (Saha et al., 2005); moreover, it represents the eighth cause of disability among young people with an important economic burden for the society (Serretti et al., 2009). The disease is characterized by frequent acute relapses, which are due to several causes. Among them, one of the most relevant is the lack of treatment compliance. Poor treatment compliance could be due to several reasons, such as lower tolerability of treatment, complexity of the medication schedule, comorbidity with alcohol consumption, demographical factors (e.g. poor social support), poor relationship with the therapist or presence of delusion of persecution, poisoning or grandeur. However, several studies showed that impaired insight represents one of the main risk factor for lack of treatment compliance (Emsley et al., 2008; Acosta et al., 2012). Consistently, it has been reported that a good insight was one of the main predictor of both a better pharmacological compliance and a better general outcome (Amador and Gorman, 1998). Unfortunately, Corresponding author at: Department of Psichiatry, University of Catania,Via Santa Sofia 78, Catania, Italy. Tel.: þ 39 0953782470; Mobile:+39 3922824098. E-mail address: [email protected] (O. Bianchini). 1 These authors contributed equally to this work.
the lack of insight is predominant among schizophrenic patients compared to other psychiatric patients (Pini et al., 2001), with a prevalence of about 56–67% of poor insight patients (Bayard et al., 2009). With the term insight we referred to a phenomenological construct, which was described for the first time in 1836 in “Lehrbuch der Psichiatrie”, a text by Krafft-Ebingis. In this text the “einsichtslos” (i.e. insight) was considered as the inability of the patient to recognize his delusional aspects (Amador and Gorman, 1998). However, the original definition of insight was enriched later with other aspects. Particularly, nowadays, multidimensional accounts of insight have been accepted within research (Konstantakopoulos et al., 2013). David (1990) proposed three distinct but partially overlapping dimensions of insight, namely the ability to recognize that one has a mental illness, compliance with treatment, and the capacity to relabel unusual mental events (e.g. delusions and hallucinations) as pathological. Other authors suggested that two major components of insight are the capacity of patient in recognizing the pathological nature of symptoms (Amador et al., 1993) or the awareness of the benefits of taking the medication (Amador et al., 1993). Thus, the concept of insight does not include only the awareness of illness, but also the capacity in examining the different levels of motivation and the acceptance of a new point of view that
http://dx.doi.org/10.1016/j.psychres.2014.03.022 0165-1781/& 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Bianchini, O., et al., Effects of antipsychotic drugs on insight in schizophrenia. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.03.022i
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could undermine their beliefs (Aguglia et al., 2002). For this reason, the modern scales developed to measure patient's insight are composed by different parts, which investigate all these aspects. Among these scales, the most used nowadays are the Schedule for the Assessment of Insight developed by David et al. (1992) and the Scale to Assess Unawareness of Mental Disorder developed by Amador and Strauss (1990). In the last years insight has been investigated in relationship with the severity of psychopathology (Hayashi et al., 1999), the acceptance of therapy (Misdrahi et al., 2012) and the cognitive impairment (Markova and Berrios, 1995). Despite some studies investigated these issues, no definitive conclusion has been drawn so far. Particularly, the relationship between insight and psychopathology is still not clear. As a matter of fact, a meta-analysis performed by Mintz et al. showed a weak association among insight and both positive and negative symptoms (Mintz et al., 2003). Unfortunately, few studies investigated the relationship between insight and global psychopathology severity, while a lot of studies investigated the association among insight and different psychopathological clusters, such as positive and negative symptomatological clusters. Particularly, some authors found that insight was inversely related to positive symptoms, while no association was found concerning the others cluster of symptoms (e.g. negative symptoms) (Kim et al., 1997; McEvoy et al., 1989). Interestingly, the study by McEvoy et al. suggested that the relationship between insight and positive symptoms varied according to the disease phase. Indeed, a relative strong correlation was found during the acute phase of the disease, while this relationship became weaker during the maintenance phase. This observation could be due to the impact of severe psychotic symptoms on the global cognition of the patient, which is related to insight as well. Consistently, from an etiological point of view, it is hard to link positive symptoms directly to insight. Indeed, the more accepted hypothesis posits that lack of insight in schizophrenic patient is due to a prefrontal impairment, which is accountable also for both the negative and cognitive symptoms (Varga et al., 2007). Nonetheless, studies which investigated the association between insight and negative symptoms did not find any correlation (Simon et al., 2009). On the other hand, some studies suggested a possible association between cognitive function impairment and poor insight (Mohamed et al., 1999), suggesting that poor insight may be mainly due to the cognitive impairment of the patient. This finding is consistent with a recent study by Wiffen et al. (2012), which suggests a strong relationship among neuropsychological deficits and poor insight. Interestingly, authors hypothesized a learning component of insight, which may be enhanced through appropriate psychological and rehabilitative treatments. Nonetheless, overall the relationship between insight and the psychopathological status has not been deeply investigated so far and further studies are required to draw definitive conclusion. Furthermore, to the best of our knowledge, very few studies were specifically carried out to investigate the effects of different antipsychotic drugs on insight. Despite some limitations in the design and quality of the existing studies on the comparative effectiveness of First Generation Antipsychotics (FGAs) and Second Generation Antipsychotics (SGAs) (e.g. most frequent comparison of SGAs only with haloperidol, heterogeneity in clinical features and population data, etc.), the latter have been proved to be more effective in improving negative symptoms (Hartling et al., 2012). On the other hand, the superiority of SGAs on FGAs on cognitive symptoms is still controversial (McKenna and Mortimer, 2014). Taking into account these data, it could be hypothesized that SGAs may have a specific effect on insight as well. Consistently, one preliminary study by Aguglia et al. showed that SGAs improved patients' insight more than FGAs (Aguglia et al., 2002). Nonetheless, the sample size of
this previous study was small and it did not allow to draw consistent conclusions as well as to compare the effects of different SGAs. However, the detection of a specific effect on this fundamental psychopathological aspect by a specific antipsychotic drug may allow to better understand the biological origin of insight and its relationship with other symptoms, also in providing important clinical information. Taking into account all these considerations, the present study was carried out to investigate the specific effect of three SGAs (aripiprazole, olanzapine, ziprasidone) and one FGA (haloperidol) on insight in a sample of schizophrenic patients, which needed a pharmacological switch for psychosis exacerbation. As secondary aims, we investigated the associations among different clusters of symptoms and insight, also considered in its distinct components, in order to provide further evidences for previous literature data.
2. Methods We included in the study 55 patients recruited at the Department of Psychiatry of University Hospital of Catania, Sicily, Italy. The diagnosis was made by two different M.D. according to the DSM-IV TR criteria. The duration of study was 6 months and there were three times of follow up: at baseline (T0), at 3 months (T1) and at 6 months (T2). All recruited patients needed a pharmacological switch for psychosis exacerbation at the inclusion in the study. All patients (18–65 years old) provided written informed consent before participating in the study. The study was carried out in accordance with the latest version of the Declaration of Helsinki. At the recruitment, patients were assigned randomly to one of the antipsychotic included in the present study. The drugs used were chosen because (1) haloperidol (HAL) is the most used FGA in our country and worldwide; (2) olanzapine (OLA) is one of the SGA with more proven efficacy (Glick et al., 2011); (3) aripiprazole (ARI) is one of the SGA that seems to have a greater effectiveness on both negative and cognitive symptoms in comparison to other SGAs (Stip and Tourjman, 2010) and (4) ziprasidone (ZIP) is one of the newest SGAs in our country and its effect on specific psychopathological features has not been deeply investigated so far (Montes, 2012). Fifteen patients were switched to OLA, 15 to HAL, 15 to ARI and 10 to ZIP. The switch was made gradually. The range of dosage of antipsychotics was 10–20 mg for OLA, 2–9 mg for HAL, 10–30 mg for ARI and 80–160 mg for ZIP. The psychopathological status of patients was measured at each visit through the administration of the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1989), by a trained rater, who was blinded to the patients' treatment. Levels of insight were assessed by the same rater through the administration of the Schedule for the Assessment of Insight (SAI) (David et al., 1992), a semi-structured interview that measures three different dimensions of insight: therapy compliance (SAI 1), awareness of illness (SAI 2) and identification of psychotic symptoms (SAI 3). The improvement at PANSS scale was calculated with the formula [(PANSS T030) (PANSS T2-30)/(PANSS T0-30)] and the improvement at SAI scale with the formula [(SAI T0) (SAIT2)/(SAIT0)]. The improvement of each PANSS and SAI subscales (respectively positive, negative and general subscales and SAI1, SAI2 and SAI3) was calculated and considered for the analyses. All data analyses were performed using the Statistica package, version 7.0 (StatSoft Italia, Vigonza, Padua, Italy) for Windowss (1995). Analysis of variance (ANOVA), analysis of co-variance (ANCOVA) and chi-square statistical analyses were performed when appropriate. All p-values were 2-tailed. GPower (http://www.psycho.uni-duesseldorf.de/aap/ projects/gpower/) was employed for the power analysis. With these parameters (p ¼ 0.05) we had a sufficient power (0.80) to detect an effect size of 0.2, that corresponded to the possibility of detecting differences on PANSS total improvement scores of two points.
3. Results The characteristics of the sample are shown in Table 1. The groups of patients, separated by the antipsychotic drugs, were homogeneous for age, sex, PANSS and SAI scores at the baseline (Table 1). Regarding insight, analyses showed that patients of the HAL group showed a lower improvement compared to SGAs patients (overall p o0.001, HAL vs OLA p o0.001, HAL vs ARI p o0.001, HAL vs ZIP p o0.001) (Fig. 1). Among the SGAs, no difference was detected in improving insight. When we controlled for possible confounding factors, we found that a higher psychopathology at the baseline predicts a higher improvement in insight (PANSS
Please cite this article as: Bianchini, O., et al., Effects of antipsychotic drugs on insight in schizophrenia. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.03.022i
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Table 1 Demographic characteristics and general analysis of the sample. Groups
Patients
Sex M (%)
Age
Doses mg/day
PANSS BSL
PANSS IMPR.%a
SAI BSL
SAI IMPR.%a
Total OLA HAL ARI ZIP
55 15 15 15 10
35 (63.6%) 10 (66.67%) 10 (66.67%) 7(46.67%) 8 (80%)
39.1 7 11 38 7 11.2 39.9 7 11.9 38.2 7 10.6 40.9 7 11.3
10–20 2–9 10–30 80–160
120.2 7 20.9 126.6 7 22.3 112.5 7 19.3 122.4 7 19.3 118.8 7 22.7
267 17 257 1 177 11 307 16 377 25
4.8 7 2.6 4.17 3.3 5.2 7 2.0 4.4 7 2.6 5.8 7 2.0
337 33 447 36 47 20 457 33 417 15
PANSS and SAI improvement percentage7S.D.
Total p o0.001, F¼ 13.54; PANSS Positive p o0.001, F¼ 13.31; PANSS Negative p o0.001, F¼14; PANSS General has no effects). Interestingly, when we controlled for psychopathological improvement, we found an effect only for improvement in negative symptomatology (p o0.001, F¼13.87). No effect of sex and age was found. Moreover, we investigated the possible relationship among each antipsychotic included in the study and the improvement of score obtained at each subscale of SAI. We found that all SGAs are more effective than HAL in improving score obtained at SAI 1 and SAI 2 (p o0.001), while no significant difference was found among them. On the other hand, no significant difference among SGAs and HAL was detected for SAI 3 (p 40.05). Regarding psychopathology, when we compared the HAL group with the SGAs group, we found a greater improvement at the PANSS total score in SGAs group (p ¼0.002). Among the SGAs investigated, no one showed a greater efficacy than the others. Interestingly, in the PANSS positive subscale, we did not find any difference between HAL and SGAs, as well as among the different SGAs investigated. On the other hand, SGAs showed overall greater efficacy in improving negative symptoms compared to HAL (p ¼0.01); particularly, OLA and ARI were more effective than HAL (respectively p ¼0.01 and p ¼0.02), while this difference was not detected comparing HAL with ZIP. Regarding the general symptomatology, we found a greater overall efficacy of SGAs on FGA (p o0.001), without any difference among the different SGAs. When we investigated the relationship between insight and psychopathology, we found an association between the improvement of insight and global psychopathology measured by PANSS (p¼0.02; R2 adj.¼0.08). Particularly, the improvement of insight was related to improvement both in negative (po0.001; R2 adj.¼ 0.19) and in general (p¼0.01; R2 adj.¼0.09) symptomatology, but not for the improvement of positive symptomatology. Particularly, we found that SAI 1 (therapy compliance) score was associated with global psychopathology (PANSS total score) and with positive symptomatology (PANSS positive subscale) (po0.001 and po0.05 respectively), while there was no association with negative and general PANSS subscales (p40.05). Regarding the score obtained at SAI 2 (awareness of illness), they were associated with PANSS total score and with the other PANSS subscales scores (po0.001 for all the results), negative subscale apart (p40.05). Finally, SAI 3 (identification of psychotic symptoms) scores were associated with PANSS positive and negative subscales scores (both po0.001), but not with the general subscale and the total PANSS scores (p40.05).
4. Discussion The aim of this study was to evaluate, in patients affected by schizophrenia, the effectiveness of different antipsychotics in improving insight and to investigate the relationship between psychopathology and insight improvements. Until now, few studies have been conducted to directly investigate the influence of pharmacological treatment on insight. Further, studies found in literature were often not specifically designated for
Insight and Drugs Current effect: F=5,3, p=,00008 13 12 11 10 9 8 SAI
a
7 6 5 4 3 2 1 T0
T1
T2
Olanzapine Haloperidol Aripiprazole Ziprasidone
Fig. 1. Insight improvement induced by the four AP drugs.
this aim and they have several methodological limitations (e.g. the use of non-validated scales in order to determine insight). Consistently, few literature data are available concerning specifically the efficacy of SGAs in improving insight in schizophrenia. In this background, our study revealed a greater improvement of the levels of insight, in a six-month period, in patients with schizophrenia treated with SGAs with respect to those treated with HAL. This finding is consistent with previous results (Aguglia et al., 2002; Rocca et al., 2008), although one previous study failed to find any differences among FGAs and SGAs as well (Sajatovic et al., 2002). However, these studies have several methodological limitations (such as small sample size, non-blinded, nonrandomized design, absence of direct comparison among different antipsychotics, etc.), which have to be considered in the interpretation of the results. Therefore, till now the suggested superiority of SGAs on FGAs in improving insight is still a matter of debate (Leucht et al., 2009; Lewis, 2009) and further specific investigation, with rigorous methodology, is needed to better dissect this issue. On the other hand, it is not completely clear how the SGAs could affect insight in schizophrenia. In our study we evaluated the effect of specific SGAs, investigating their impact in comparison with HAL, taking into account the different psychopathological dimensions of schizophrenia, which in turn could directly affect insight (e.g. negative symptomatology). All three SGAs were found to be more effective than HAL in improving the global symptoms at the PANSS. The trend of such improvement also reflects on insight, which improved significantly with all three SGAs compared to HAL; the three SGAs resulted in greater improvement of insight comparatively. Therefore, improvement of insight with SGAs could be, at least partially, due to the psychopathological improvement rather than a specific effect of these drugs on insight itself. In particular, when we compared the effectiveness of the four antipsychotics with the three distinct subscales of SAI, we found that SGAs are more effective than HAL on the component concerning the therapy compliance and the awareness of illness (SAI 1 and SAI 2 respectively), while no
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O. Bianchini et al. / Psychiatry Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎
significant difference has been found concerning the identification of psychotic symptoms as well as non-physiological phenomena (SAI 3). This latter result might be consistent with the finding that, at the breakdown of the symptomatological dimensions at PANSS, significant differences among the various drugs did not emerge concerning the positive symptomatology. On the other hand, SGAs showed greater effects on both general and negative symptoms compared to HAL, although for ZIP the difference was not significant regarding negative symptoms. The lack of a relevant difference, in terms of efficacy, between FGAs and SGAs on positive symptoms found in our study, could suggest that this psychopathological dimension may not be related, at least in the post-acute phase of the disease, to improvement in insight. This finding is consistent with previous results (McEvoy et al., 1989). On the contrary, we found a higher efficacy of SGAs on negative symptoms and though only 19%, we also detected a positive association between improvement of such psychopathological dimension and improvement of insight. Negative symptoms of schizophrenia are widely suspected to reflect a frontal lobe dysfunction (Semkovska et al., 2001) and different studies associated with insight to poor cognitive performance and damage of the prefrontal cortex (Aleman et al., 2006). The hypothesis that SGAs have a positive impact on specific cognitive functions (Keefe et al., 1999; Woodward et al., 2005), could explain the better response of negative symptoms and the improvement of the insight levels observed in our study with these drugs. The higher efficacy of SGAs on negative symptoms could partially explain their effects on insight. Indeed, we detected differences among SGAs about the efficacy on negative symptoms (OLA and ARI resulted superior to ZIP) but not concerning the efficacy in improving insight, not even when we consider the three distinct dimensions detected by SAI. This finding is consistent with previous reports (Mintz et al., 2003), suggesting a possible independence between the two domains. Further, despite the significant association observed between psychopathology and insight, the association is far than complete and many aspects still need to be clarified. For example, insight may be related to other psychopathological domains, such as anxiety and depressive symptomatology, which are common symptoms in schizophrenia and they could be due to several factors (Ekinci et al., 2012). Therefore, other neurobiological mechanisms of action of the SGAs may be involved in the observed insight improvement, likely involving specific brain regions related to insight. Such results sustain the hypothesis that insight could be considered a specific psychopathological dimension of schizophrenia, which is not entirely associated to other symptoms. To the best of our knowledge, this is the first study that investigated, beside the association between insight and other psychopathological domains, the impact of the single antipsychotic drugs on the insight levels. Furthermore, the study was designed specifically for this aim, as demonstrated by the use of SAI, which is a validated scale studied upon a large range of clinical samples. Unfortunately, the extended version of this scale, (SAI-E) (Kemp and David, 1997), which is more detailed, has not yet been available in Italian. Our study has several limitations, mainly the relatively small sample size. Furthermore, patients included in our sample had different duration of illness; clearly, the duration of illness also impacts the insight dimension (McEvoy et al., 2006), although the effect of this factor is still not clear (i.e. a longer disease may be related to a better insight as well as to the contrary, according to several other variables such as the relationship with the Psychiatric service, the response to treatment and so on). Unfortunately, data about the duration of illness were lacking; indeed all patients included needed a switch from another AP, but we did not collect data about duration of illness and thus we were not able to consider this relevant variable in the analyses. Lastly, the use of
the Scale to assess Unawareness of Mental Disorder (SUMD) (Amador and Strauss, 1990) in order to measure insight, being a scale with 74 items and largely approved as a multidimensional measuring system of insight, may have provided more information than SAI on specific components of insight. Additional studies with a larger sample and a randomized design are needed, in order to characterize the role and efficacy of antipsychotic drugs on the levels of insight in patients with schizophrenia. A clearer definition of the insight dimension within schizophrenia, including drug treatment that mostly affects insight, has also an important role in relation to the evidence of an association between insight and compliance, since a large percentage of patients with schizophrenia are not compliant to the drug treatment (Fenton et al., 1997; Lacro et al., 2002). In conclusion, this trial showed that SGAs seem to have a relevant impact on the improvement of the insight levels. Higher evidence could provide indications about what antipsychotic should be used in specific populations of patients with lack of insight. The mechanisms that indicate a better impact of the SGAs on the levels of insight could be manifold and derived from specific drug receptor profiles. Finally, considering the association between insight and cognitive symptoms, the development of new and targeted therapies to improve cognition in schizophrenia, might play an important role in improving insight as well. In this regard, a list of potential targets of cognitive-enhancing drugs has been promulgated by the MATRICS Consensus meeting, and it includes alfa7-nicotin receptor agonists, D1 receptor agonists, AMPA glutamatergic receptor agonists, alfa2-adrenergic receptor agonists, metabotropic glutamate receptor agonists glycine reuptake inhibitors, M1 receptor agonists and GABA A receptor subtype selective agonists (Green, 2007). Further research oriented in investigating specific associations among antipsychotics with different receptor's profiles, specific cognitive functions, psychopathology, time of treatment and insight, could provide important data on the brain regions implicated in these processes and on developing new and specific therapeutic interventions to improve insight at different stages of schizophrenia.
Role of funding source None.
Conflict of interest Prof. Serretti is or has been the consultant/speaker for: Abbott, Astra Zeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Pfizer, Sanofi, Servier. References Acosta, F.J., Hernandez, J.L., Pereira, J., Herrera, J., Rodriguez, C.J., 2012. Medication adherence in schizophrenia. World Journal of Psychiatry 2 (5), 74–82. Aguglia, E., De Vanna, M., Onor, M.L., Ferrara, D., 2002. Insight in persons with schizophrenia: effects of switching from conventional neuroleptics to atypical antipsychotics. Progress in Neuro-Psychopharmacology and Biological Psychiatry 26 (7–8), 1229–1233. Aleman, A., Agrawal, N., Morgan, K.D., David, A.S., 2006. Insight in psychosis and neuropsychological function: meta-analysis. British Journal of Psychiatry 189, 204–212. Amador, X.F., Gorman, J.M., 1998. Psychopathologic domains and insight in schizophrenia. Psychiatric Clinics of North America 21 (1), 27–42. Amador, X.F., Strauss, D.H., Yale, S.A., Flaum, M.M., Endicott, J., Gorman, J.M., 1993. Assessment of insight in psychosis. American Journal of Psychiatry 150 (6), 873–879.
Please cite this article as: Bianchini, O., et al., Effects of antipsychotic drugs on insight in schizophrenia. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.03.022i
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Please cite this article as: Bianchini, O., et al., Effects of antipsychotic drugs on insight in schizophrenia. Psychiatry Research (2014), http://dx.doi.org/10.1016/j.psychres.2014.03.022i
