|Year : 2020 | Volume
| Issue : 2 | Page : 154-158
An observational study of clinical subtypes in treatment-resistant schizophrenia and its relation with cognitive insight
Kundan Sandipan Kamble1, Ajita Sunil Nayak2, Arun Vivekananth Kumar3
1 Department of Psychiatry, Dr. V.M.G.M.C., Solapur, Maharashtra, India
2 Department of Psychiatry, Seth G.S. Medical College, KEM Hospital, Parel, Mumbai, Maharashtra, India
3 Department of Psychiatry, Sree Mookambika Institute of Medical Sciences Hospital, Kulasekharam, Kanyakumari, Tamil Nadu, India
|Date of Submission||25-Feb-2020|
|Date of Decision||16-Mar-2020|
|Date of Acceptance||06-Jun-2020|
|Date of Web Publication||24-Sep-2020|
Dr. Kundan Sandipan Kamble
Department of Psychiatry, Dr. V.M.G.M.C., Solapur, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Schizophrenia is a chronic disorder, and one-third of patients with schizophrenia can develop treatment resistance. Factors such as male gender, early age of onset, positive family history, and low level of social functioning are associated with refractoriness to treatment. However, very few Indian studies have tried to establish the predictors of outcome for schizophrenia. Aims: The aim of the study was to identify the subtypes of treatment-resistant schizophrenia (TRS) and its relation with sociodemographic profile, illness-related variables, and cognitive insight. Materials and Methods: The study was conducted after permission from the institutional review board. Fifty consecutive patients of TRS (treated with two antipsychotics from different classes with adequate doses for 6 weeks each and currently satisfying the Diagnostic and Statistical Manual of Mental Disorders 4th Edition, Text Revision criteria for schizophrenia) were included in the study. Patients were administered a semi-structured questionnaire to obtain details about sociodemographic status, and the Positive and Negative Syndrome Scale was administered to identify the subtypes of schizophrenia. Becks Cognitive Insight Scale was used to assess cognitive insight. Results: Almost half of the sample (46%) belonged to the positive subtype followed by negative subtype. There was a statistically significant difference in the age of onset, educational qualification, and suicidal ideation between the positive and negative subtypes. There was a significant association of cognitive insight between TRS subtypes, and it suggested that patients with positive subtype had poorer insight than those with negative subtype. Conclusions: It is important to identify the subtype of schizophrenia and the risk factors for treatment resistance. Early recognition and intervention with respect to these risk factors can improve the long-term course of TRS.
Keywords: Clinical subtypes, cognitive insight, treatment-resistant schizophrenia
|How to cite this article:|
Kamble KS, Nayak AS, Kumar AV. An observational study of clinical subtypes in treatment-resistant schizophrenia and its relation with cognitive insight. Ann Indian Psychiatry 2020;4:154-8
|How to cite this URL:|
Kamble KS, Nayak AS, Kumar AV. An observational study of clinical subtypes in treatment-resistant schizophrenia and its relation with cognitive insight. Ann Indian Psychiatry [serial online] 2020 [cited 2021 Jan 17];4:154-8. Available from: https://www.anip.co.in/text.asp?2020/4/2/154/295908
| Introduction|| |
Schizophrenia is a chronic disorder of body and mind that affects 5.5/1000 of the population. Poor compliance with drug treatment is a frequent problem among schizophrenia patients. Side effects such as extrapyramidal symptoms, sexual dysfunction, and weight gain along with lack of insight are the major causes leading to noncompliance., However, despite adequate pharmacological treatment, between 1/3rd and 1/2nd who meet the diagnostic criteria of schizophrenia remain ill.
These patients are classified as treatment-resistant schizophrenia (TRS), which has been defined as patients not responding to adequate doses of two antipsychotics from different groups for a period of 6 weeks. It has been estimated that cases of TRS can be 20%–50% of the total.,
Various factors studied in the past have been suggested to lead to poor response to treatment in patients with schizophrenia. Epidemiological data revealed that male gender, early age of onset, positive family history, obstetric complications, absence of affective symptoms, negative symptoms, etc., could be associated with some degree of treatment refractoriness.
Recent literature has suggested that TRS itself is a heterogeneous disease with varied prevalence. Various studies have compared subgroups within TRS patients based on clinical factors with the aim of improving the diagnosis and treatment of TRS patients. TRS patients can be subgrouped based on the age of onset, number of suicide attempts, etc. However, comprehensive studies comparing TRS patients based on the clinical features of positive symptoms with those of negative symptoms are lacking.
The comparisons between positive and negative subtypes of schizophrenia have found negative symptomatology to be associated with early age of onset,, poor educational level, and poorer outcome. As treatment response is associated with clinical subtype, studying various sociodemographic and illness-related risk factors associated with the subtypes in the TRS patients could help in the early diagnosis of treatment resistance.
Another factor associated with treatment response is cognitive insight., “Cognitive insight” is defined as a patient's current capacity to evaluate his or her anomalous experiences and atypical interpretations of events. Patients with schizophrenia, especially deluded patients, were proposed to have limited capacity for evaluation of their erroneous inferences, and they seem to be relatively resistant to corrective feedback. Even though patients may accept an illness explanation for their symptoms and agree that this explanation makes sense (intellectual insight), still this may not produce any significant change in their underlying belief system (cognitive insight). Cognitive insight in schizophrenia patients is reported to be related to the current symptoms and stage of the illness.
Hence, we conducted this study in TRS patients to identify the differences in cognitive insight, sociodemographic variables, and illness-related variables among patients with positive and negative subtypes.
| Methods|| |
It was an observational study done at a tertiary care hospital after institutional ethical committee approval, designed in accordance with the Declaration of Helsinki. Treatment-resistant patients in the age group of 18–50 years fulfilling the Diagnostic and Statistical Manual of Mental Disorders 4th Edition, Text Revision (DSM-IV-TR) criteria for schizophrenia and treated by two antipsychotics from different classes with adequate doses for 6 weeks each were included in the study. Patients of age >50 years and <18 years as well as noncompliant patients were excluded from the study.
A total of fifty patients diagnosed with TRS in the psychiatry outpatient department of a tertiary care hospital fulfilling the above inclusion and exclusion criteria and who gave consent, were selected for the study as cases in a period of 2 years. They were administered semi-structured questionnaires to obtain details about sociodemographic status and illness-related variables. The DSM-IV-TR was used to diagnose schizophrenia and to identify the presence of affective features and psychiatric comorbidities. The Positive and Negative Syndrome Scale (PANSS) was administered to identify the various clinical subtypes namely positive, negative, and mixed. The negative score was subtracted from the positive score to give a composite score. A PANSS composite score of <−3 was required for inclusion in the negative symptom group and a PANSS composite score of >+3 was required for inclusion in the positive symptom group. Patients with mixed pictures have PANSS composite scores between −3 and +3.
Patients diagnosed with positive symptoms were compared with patients diagnosed with negative symptoms on PANSS.
Becks Cognitive Insight Scale (BCIS) was used to assess insight. It is a self-report inventory consisting of 15 statements rated on a 4-point Likert scale. Based on factor analyses, the scale was divided into two subscales. The self-reflectiveness subgroup consists of nine items and the self-certainty subgroup consists of six items. The self-reflectiveness items of the BCIS assess objectivity, reflection, and openness to feedback, whereas the six self-certainty items tap certainty about being right and resistance to correction. Ahigh score on the subscale of self-reflectiveness and a low score on the subscale of self-certainty is considered as normal. A composite cognitive insight index score (Composite Index) is obtained by subtracting the self-certainty score from the self-reflectiveness score.
Statistical analysis was done using SPSS software version 17 (IBM, New York, USA). Qualitative data (gender, occupation, etc.) were described with frequency and percentages and were compared using Chi-square test/Fisher's exact test. Quantitative data (age, BCIS, etc.) were described as mean and standard deviation and were compared using Student's t-test. P < 0.05 was considered statistically significant.
| Results|| |
On PANSS scoring, almost half of the sample belonged to the positive subtype (46%) followed by negative (32%) and least was mixed subtype (22%), as shown in [Table 1]. There was a statistically significant difference in the age of onset and educational qualification between the positive and negative subtypes. Only one patient of negative subtype had suicidal ideation, whereas eight patients among positive subtype had suicidal ideation. This difference was also statistically significant (P = 0.04). The other demographic factors showed no significant difference [Table 2]. On BCIS, the positive subgroup had a mean self-reflectiveness score of 10.95 and a self-certainty score of 14.04. The negative subtype had a self-reflectiveness score of 13.62 and a self-certainty score of 12.5. As shown in [Table 3], there was a significant difference of cognitive insight between TRS subtypes, and it suggested that positive subtype was associated with poorer insight than negative subtype.
|Table 1: Distribution of subtypes on the Positive and Negative Syndrome Scale|
Click here to view
|Table 3: Becks Cognitive Insight Scale Composite Index and subtype (n=39)|
Click here to view
| Discussion|| |
About 30% of patients with schizophrenia do not show adequate response to treatment and are diagnosed as treatment resistant. Farooq et al. have proposed that this differential treatment response constitute a biologically distinct type of schizophrenia. A study into the clinical subtypes of TRS and differences among them could help in individualized treatment of TRS patients.
On applying the PANSS in our sample of TRS patients, we found that 46% belonged to the positive subtype, 32% were of the negative subtype, while only 22% the mixed subtype. These findings differed from the general patients of schizophrenia where almost an equal number of patients have been reported to belong to the positive, negative, and mixed subtypes., Thus, the prevalence of both positive and negative subtype was found to be higher in patients with poor treatment outcome as compared to the other patients of schizophrenia.
On comparing between the positive and negative subtypes of TRS patients, earlier age of onset of illness was found to be present significantly higher in the positive subtype than the negative subtype group. Low education level was also found to be significantly higher in the positive subtype. Studies in general schizophrenia patients have reported negative subtype of schizophrenia to be associated with early age of onset, and poor educational level., Thus, in TRS patients, these risk factors may play a significant role in the outcome independent of the subtype of schizophrenia.
In 2012, a systematic review of early-onset schizophrenia found that early onset of illness had poor outcome compared to mixed group where the onset was after 21 years.
In a nationwide cohort study by Hakulinen et al., diagnosis of schizophrenia by 15 years of age had six times higher risk of having poor education as compared to diagnosis of schizophrenia by 25 years.
Early age of onset might have a detrimental effect on outcome because of impact at very crucial times of development and neurobiological maturation in childhood and adolescent age, which prove to have more lasting effects in terms of cognitive and psychosocial functioning. The cognitive deficit also precedes the onset of illness and may begin at early age and thus results in poor education level. Further studies could elucidate the correlation of these factors and psychopathology in the prognosis of schizophrenia.
In our study, we found a significant association between suicidal ideation and subtypes; the positive subtype was found to have more suicidal ideation than negative subtype (P = 0.04). Similar findings have been reported in studies in general schizophrenia patients that patients who died due to suicide had significantly lower negative symptom severity at index admission than patients without suicidal behaviors. The paranoid schizophrenia subtype was associated with an elevated risk (12%) and the deficit subtype was associated with a reduced risk (1.5%) of suicide.
Studies in general schizophrenia patients have suggested an association between schizophrenia subtype and suicide risk. Data suggest that negative symptoms, when present as a prominent component of illness, are associated with a significantly lower long-term risk of suicide among patients with schizophrenia. The nondeficit subtype of schizophrenia, which is based on the absence of enduring negative symptoms, defines a group of patients whose risk for suicide is six times greater than that of patients with the deficit subtype. Conversely, two positive symptoms (suspiciousness and delusions) appear to be associated with an elevated long-term risk of suicide. The paranoid subtype of schizophrenia which emphasizes positive symptoms and the absence of negative symptoms, is associated with a suicide risk that is eight times greater than the risk associated with the deficit subtype and three times greater than the nonparanoid subtypes. It has been found that patients who committed suicide had less negative symptoms, while those with no suicidal ideation or behavior had high negative symptoms. Those patients with suicidal ideations and attempts had only few negative symptoms and in fact may actually just be a subset of patients who complete suicide.
Patients with schizophrenia are at high risk of suicide. Cognitive behavioral therapy (CBT) has been shown to reduce symptoms in schizophrenia. In a study by Bateman et al. in 2007, the authors found that CBT provided significant reductions in suicidal ideation. Patients of positive subtypes have shown to have more suicidal ideation, and CBT could be helpful for such patients of TRS.
Long-term studies of patients with schizophrenia have found variable outcomes based on the clinical subtypes. Patients with many negative symptoms were found to have insidious onset, poor premorbid functioning, partial or no remissions during the first several years of illness, and, in most cases, a progressive course leading to permanent disability. In another study conducted on TRS patients, the authors have found total course of disease shorter in the positive group while onset of the mixed and negative groups were chronic and frequencies of hospitalization more.
Another factor we studied in our patients of TRS was insight. They were found to have a poor awareness into their illness and treatment as indicated by a higher self-certainty score compared to self-reflection. We also found a statistically significant correlation between the BCIS composite index and clinical symptoms (P = 0.047). Thus, positive subtype was found to have significantly poor insight compared to negative subtype. Studies which have examined the relationship between insight and symptoms in schizophrenia have demonstrated the existence of a negative correlation between insight and the severity of positive symptomatology.,, Carroll et al. also indicated that better insight was significantly correlated with fewer positive symptoms. In a comprehensive meta-analysis, Lincoln et al. found that between 50% and 80% of individuals suffered from partial or complete lack of insight. Poor insight in schizophrenia has been proposed to result in poor social and interpersonal functioning, poor treatment compliance,, and higher risk of relapse. Research has indicated that poor cognitive insight may be associated with poor outcome in schizophrenia patients. Lack of awareness of the illness and its social consequences has been reported to be only correlated with the positive dimension, while lack of awareness of achieved effects of medication has been correlated with the autistic preoccupation factor.
A study by Perivoliotis et al. showed that improvements in self-reflectiveness, self-certainty, and the Composite Index score of the BCIS were significantly correlated with concomitant reductions in the severity of both delusions and hallucinations. These symptoms are mainly present in the positive subtype of schizophrenia and this subtype have poorer cognitive insight, so interventions to improve the cognitive insight might have improvement in treatment outcome in patients with TRS.
| Conclusions|| |
The present study showed that majority of the TRS patients had positive subtype of schizophrenia in comparison to negative and mixed types. Suicidal ideations, early age of onset, and low education level were significantly higher in the positive subtype of TRS as compared to negative subtype. Cognitive insight was found to be significantly poorer in patients with positive subtype as compared with negative subtype.
Management of TRS patients has remained a persistent public health problem. Hence, it is important to identify risk factors early. It is also important to differentiate between TRS positive and negative subtypes as risk factors for each are different. Suicidal ideation and poor insight are more significantly associated with the positive subtype of TRS. Early detection and intervention of these risk factors can improve the long-term course of TRS.
As this study was conducted in a tertiary hospital, it may not be representative of the general population. The sample size of the present study was small, and future studies are needed in a larger population.
This study was approved by the institutional ethical committee with reference number EC/96/2012 obtained on July 27, 2012.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient's guardian has given her consent for herthe patient's images and other clinical information to be reported in the journal. The patient's guardian understands that the patient's name and initials will not be published, and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Goldner EM, Hsu L, Waraich P, Somers JM. Prevalence and incidence studies of schizophrenic disorders: A systematic review of the literature. Can J Psychiatry 2002;47:833-43.
Grover S, Chakrabarti S, Kulhara P, Avasthi A. Clinical practice guidelines for management of schizophrenia. Indian J Psychiatry 2017;59:S19-33.
Marder SR. Antipsychotic drugs and relapse prevention. Schizophr Res 1999;35 Suppl:1, S8792.
Fleischhacker WW, Meise U, Günther V, Kurz M. Compliance with antipsychotic drug treatment: Influence of side effects. Acta Psychiatr Scand Suppl 1994;382:11-5.
Juarez-Reyes MG, Shumway M, Battle C, Bacchetti P, Hansen MS, Hargreaves WA. Effects of stringent criteria on eligibility for clozapine among public mental health clients. Psychiatr Serv 1995;46:801-6.
Elkis H, Meltzer HY. Refractory schizophrenia. Braz J Psychiatry 2007;29 Suppl 2:S41-7.
Lally J, Ajnakina O, Di Forti M, Trotta A, Demjaha A, Kolliakou A, et al
. Two distinct patterns of treatment resistance: Clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Psychol Med 2016;46:3231-40.
Frank J, Lang M, Witt SH, Strohmaier J, Rujescu D, Cichon S, et al
. Identification of increased genetic risk scores for schizophrenia in treatment-resistant patients. Mol Psychiatry 2015;20:150-1.
Malaspina D, Goetz RR, Yale S, Berman A, Friedman JH, Tremeau F, et al
. Relation of familial schizophrenia to negative symptoms but not to the deficit syndrome. Am J Psychiatry 2000;157:994-1003.
Alvir JM, Woerner MG, Gunduz H, Degreef G, Lieberman JA. Obstetric complications predict treatment response in first-episode schizophrenia. Psychol Med 1999;29:621-7.
Rieckmann N, Reichenberg A, Bowie CR, Parrella M, White L, Friedman JI, et al
. Depressed mood and its functional correlates in institutionalized schizophrenia patients. Schizophr Res 2005;77:179-87.
Correll CU, Brevig T, Brain C. Exploration of treatment-resistant schizophrenia subtypes based on a survey of 204 US psychiatrists. Neuropsychiatr Dis Treat 2019;15:3461-73.
Immonen J, Jääskeläinen E, Korpela H, Miettunen J. Age at onset and the outcomes of schizophrenia: A systematic review and meta-analysis. Early Interv Psychiatry 2017;11:453-60.
Kao YC, Liu YP. Effects of age of onset on clinical characteristics in schizophrenia spectrum disorders. BMC Psychiatry 2010;10:63.
Beck AT, Baruch E, Balter JM, Steer RA, Warman DM. A new instrument for measuring insight: The Beck Cognitive Insight Scale. Schizophr Res 2004;68:319-29.
Pedrelli P, McQuaid JR, Granholm E, Patterson TL, McClure F, Beck AT, et al
. Measuring cognitive insight in middle-aged and older patients with psychotic disorders. Schizophr Res 2004;71:297-305.
Bredemeier K, Beck AT, Grant PM. Exploring the temporal relationship between cognitive insight and neurocognition in schizophrenia: A prospective analysis. Clin Psychol Sci 2018;6:76-89.
Freitas R, Dos Santos B, Altamura C, Bernasconi C, Corral R, Evans J, et al
. Can the Positive and Negative Syndrome scale (PANSS) differentiate treatment-resistant from non-treatment-resistant schizophrenia? A factor analytic investigation based on data from the Pattern cohort study. Psychiatry Res 2019;276:210-7.
Farooq S, Agid O, Foussias G, Remington G. Using treatment response to subtype schizophrenia: Proposal for a new paradigm in classification. Schizophr Bull 2013;39:1169-72.
Kota SK, Kulhara P. A clinical study of positive and negative subtypes of schizophrenia. Indian J Psychiatry 1988;30:355-61.
] [Full text]
Lindenmayer JP, Kay SR, Opler L. Positive and negative subtypes in acute schizophrenia. Compr Psychiatry 1984;25:455-64.
Gold JM, Waltz JA, Matveeva TM, Kasanova Z, Strauss GP, Herbener ES, et al
. Negative symptoms and the failure to represent the expected reward value of actions: Behavioral and computational modeling evidence. Arch Gen Psychiatry 2012;69:129-38.
Clemmensen L, Vernal DL, Steinhausen HC. A systematic review of the long-term outcome of early onset schizophrenia. BMC Psychiatry 2012;12:150.
Hakulinen C, McGrath JJ, Timmerman A, Skipper N, Mortensen PB, Pedersen CB, et al
. The association between early-onset schizophrenia with employment, income, education, and cohabitation status: Nationwide study with 35 years of follow-up. Soc Psychiatry Psychiatr Epidemiol 2019;54:1343-51.
Fenton WS, McGlashan TH, Victor BJ, Blyler CR. Symptoms, subtype, and suicidality in patients with schizophrenia spectrum disorders. Am J Psychiatry 1997;154:199-204.
Hor K, Taylor M. Suicide and schizophrenia: A systematic review of rates and risk factors. J Psychopharmacol 2010;24:81-90.
Bateman K, Hansen L, Turkington D, Kingdon D. Cognitive behavioral therapy reduces suicidal ideation in schizophrenia: Results from a randomized controlled trial. Suicide Life Threat Behav 2007;37:284-90.
Fenton WS, McGlashan TH. Natural history of schizophrenia subtypes. II. Positive and negative symptoms and long-term course. Arch Gen Psychiatry 1991;48:978-86.
Yang HC, Li YP, Sheng L; Shenzhen Mental Health Institute. The comparison between Raven's standard progressive matrices and Wechsler intelligence scale for children. Chin J Behav Med Sci 2005;5.
Mintz AR, Dobson KS, Romney DM. Insight in schizophrenia: A meta-analysis. Schizophr Res 2003;61:75-88.
Weiler MA, Fleisher MH, McArthur-Campbell D. Insight and symptom change in schizophrenia and other disorders. Schizophr Res 2000;45:29-36.
Young DA, Davila R, Scher H. Unawareness of illness and neuropsychological performance in chronic schizophrenia. Schizophr Res 1993;10:117-24.
Carroll A, Fattah S, Clyde Z, Coffey I, Owens DG, Johnstone EC. Correlates of insight and insight change in schizophrenia. Schizophr Res 1999;35:247-53.
Lincoln TM, Lüllmann E, Rief W. Correlates and long-term consequences of poor insight in patients with schizophrenia. A systematic review. Schizophr Bull 2007;33:1324-42.
Smith TE, Hull JW, Goodman M, Hedayat-Harris A, Willson DF, Israel LM, et al
. The relative influences of symptoms, insight, and neurocognition on social adjustment in schizophrenia and schizoaffective disorder. J Nerv Ment Dis 1999;187:102-8.
Lysaker PH, Bell MD, Bryson G, Kaplan E. Neurocognitive function and insight in schizophrenia: Support for an association with impairments in executive function but not with impairments in global function. Acta Psychiatr Scand 1998;97:297-301.
Kazadi NJ, Moosa MY, Jeenah FY. Factors associated with relapse in schizophrenia. South Afr J Psychiatry 2008;14:52-62.
Perivoliotis D, Grant PM, Peters ER, Ison R, Kuipers E, Beck AT. Cognitive insight predicts favorable outcome in cognitive behavioral therapy for psychosis. Psychosis 2010;2:23-33.
[Table 1], [Table 2], [Table 3]