Response of Antipsychotic Drugs in Late-onset and Early-onset Schizophrenia in the Vindhya Region, Central India: A Prospective Cohort Study

1. Senior Resident, Department of Psychiatry, Gandhi Medical College, Bhopal, Madhya Pradesh, India. 2. Senior Resident, Department of Psychiatry, Shyam Shah College, Rewa, Madhya Pradesh, India. 3. Senior Resident, Department of Psychiatry, Shyam Shah College, Rewa, Madhya Pradesh, India. 4. Senior Resident, Department of Psychiatry, Nandkumar Singh Chouhan Government Medical College, Khandwa, Madhya Pradesh, India.

Abstract

Introduction: Previous studies were predominantly on early-onset schizophrenia with little emphasis on clinical profile, therapeutic responsiveness and various investigational, biochemical and neuroimaging variables in Late-onset Schizophrenia (LOS), which is an emerging concern in elderly morbidity, and differs significantly from Early-onset Schizophrenia (EOS).

Aim: To study the clinical profile, and response to various antipsychotic drugs in LOS and compare it with EOS.

Materials and Methods: A clinical prospective cohort study was conducted in Shyam Shah Medical College, Rewa Madhya Pradesh, India, from January 2020 to June 2021, with baseline and follow-up assessment of psychotic and cognitive symptoms after four weeks using PANSS (Positive and Negative Syndrome Scale), MoCA (Montreal Cognitive Assessment) and BPRS (Brief Psychiatric Rating Scale) scales. A total of 51 patients were included in the study, divided into two groups of early and late-onset, attending the outpatient and inpatient services during the period at the centre and concomitant treatment with antipsychotics for four weeks. Statistical analysis was done in Statistical Package for Social Sciences (SPSS) version 21.0 with p-value of 0.05 as significant.

Results: A total of 51 patients, 27 in EOS group and 24 in LOS were included and analysed in the present study. The demographic profile of late and EOS varied in mean age with EOS at 30.11 years and LOS at 57.66 years), gender distribution predominantly males (n=19) in EOS and predominantly females (n=20) in LOS) and the average age of onset of EOS was 22.05 years and LOS was 55.54 years. The duration of illness in EOS 7.98 years and LOS was 2.12 years. The mean PANSS score at baseline for EOS was 1.92±1.07 and LOS was 2.83±0.56 and four weeks for EOS was 1.70±0.91 and LOS was 2.83±0.56. The response in PANSS at four weeks as well as individual domain scale score such as hallucinations, suspiciousness, blunted effect, emotional withdrawal, active social avoidance showed significant results in both EOS and LOS.

Conclusion: Schizophrenia can manifest for the first time in late life and manifestations of stringently defined schizophrenia is by no means confined to onset at younger ages. Although there are undoubted similarities between the symptoms of EOS and LOS, there are also clear differences, especially demographic and clinical characteristics, early identification of which will help in adequate intervention and prevention of further morbidity in the elderly.

Clinical profile, Cognition, Rating scales

Schizophrenia though considered a disease of late adolescence and early adulthood (1) lately, the emergence of late-onset schizophrenia has become a major clinical concern, especially amongst the elderly populations. Schizophrenia is a chronic and severe mental disorder affecting twenty million people worldwide (2). A review of studies on late-onset schizophrenia found that around twenty-three percent of patients with schizophrenia were accounted to have encountered the onset of the illness after age forty, with thirteen percent in the fifth decade of life, seven percent in the sixth decade, and three percent in later decades (3),(4). Among people aged 45-64 years, there is an incident rates of twelve point six (12.6) per 100,000 every year for new-onset schizophrenia. (4). Schizophrenics are two to three times more likely to die earlier than the general population, which is often due to preventable physical diseases, including cardiovascular disorders, metabolic disease, and infections (5).

Though Dopamine is a key neurochemical in the pathophysiology of schizophrenia, with advancing age possibility of other non dopaminergic pathophysiological factors also comes into focus, thus giving distinct characteristics to late-onset schizophrenia (6). Late-onset schizophrenia also poses a diagnostic dilemma due to the existence of various degenerative disorders and other functional psychiatric disorders in old age, owing to which there are no separate diagnostic guidelines for late-onset schizophrenia in either ICD-10 DCR (International Classification of Diseases Diagnostic Criteria for Research-10) or DSM-5 (Diagnostic and Statistical Manual of mental disorders-5) (7),(8).

Despite these problems, a relatively consistent clinical picture has been reported. Schizophrenia is a blend of trademark positive symptoms (delusions, hallucinations, conceptual disorganisations, etc.) and negative symptoms (apathy, blunting of affect, poor interaction, etc.) related with cognitive impairment and marked social or occupational dysfunction. Patients with the late-onset form, be that as it may, would in general have more persecutory delusions with and without hallucinations, organised delusions, and abusive auditory hallucinations or hallucinations with a running commentary (9). The course of late-onset schizophrenia is usually chronic but may be interrupted by partial remissions and exacerbations. Patients may be quite responsive to antipsychotics used in lower doses like Risperidone (0.5 mg to 2 mg) Haloperidol (up to 5mg), Olanzapine (up to 5 mg), etc (10),(11). Elderly patients are more susceptible to certain antipsychotic side-effects, such as sedation, anticholinergic toxicity, and extrapyramidal symptoms. Atypical antipsychotics have become the agents of choice for older adults with psychosis, owing to their improved side-effect profile compared to conventional agents (12). In terms of DALYs (Disability Adjusted Life Years), schizophrenia ranked eighth, accounting for two-point six (2.6) percent of the total, and in terms of Years Lost to Disability (YLD), it was third, accounting to four-point nine (4.9) percent of the total (13),(14).

It is therefore imperative to study the clinical profile, therapeutic responsiveness, and various investigational, biochemical, and neuroimaging variables in LOS in light of well-recognised EOS. Also, there is a dearth of data comparing EOS and LOS in Vindhya region which encompasses a large number of schizophrenia patients. Thus, the objective is (i) to study the clinical profile of LOS and EOS and (ii) the comparison of response to various antipsychotic drugs in LOS and EOS. The authors hypothesise that there will be a significant difference between both groups in terms of clinical profile and response.

Material and Methods

The present study was a clinical prospective cohort study from January 2020 to June 2021, took place at the Department of Psychiatry of Shyam Shah Medical College and Sanjay Gandhi Medical Hospital, Rewa, Madhya Pradesh, India, comprising of outpatient as well as inpatient subjects (total 51). The study was commenced after the approval from the department’s scientific committee and Institutional Ethical and Scientific Committee (letter no. 9470/SS/PG/MC/2019).

Inclusion criteria: Patients of either sex, aged 16 years and above, giving, informed consent, and fulfilling the criteria of schizophrenia disorder according to ICD-10 DCR (7) were included in the study.

Exclusion criteria: Patients with overt organic brain syndromes, space-occupying lesions, serious medical illness needing hospitalisations, co-morbid substance intake in dependence pattern and needing acute emergency treatment for physical/psychotic disorder were excluded from the study.

Considering the previous admission of LOS (two-three patients per month) 30 patients of late-onset and 30 patients of EOS were selected by purposive sampling according to the inclusion and exclusion criteria mentioned above. LOS has been defined as the onset of schizophrenia after 45 years, whereas, EOS as the onset before 18 years (15),(16).

Study Procedure

After explanation of the rationale of the study and getting proper consent from patients and legally authorised representatives (such as family members), a thorough history, general, systemic and mental status examination was done to confirm the diagnosis and to record various socio-demographic clinical variables like age, gender, religion, marital status, socio-economic status, using Modified Kuppuswamy socio-economic scale, 2019 etc (17). Baseline investigations of complete blood haemogram, liver function, renal function, lipid profile, glucose level, serum electrolytes and electrocardiogram were done. Severity of psychosis and cognition was assessed on various rating scales (Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), Montreal Cognitive Assessment (MoCA), scored on baseline, and at 4 weeks as most antipsychotics show response by this time (18),(19).

Modified Brief Psychiatric Rating Scale (M-BPRS, John E. Overall and Donald R. Gorham, 1962): is a 18 item scale, scoring range from 1 (not present) to 7 (extremely severe).

Positive And Negative Syndrome Scale (PANSS, Stanley Kay, Lewis Opler and Abraham Fiszbein, 1987): is a 30-item scale (7 items each for positive and negative symptoms and 16 items for general psychopathological symptoms) scoring range from 1 (absent) to 7 (extreme).

Montreal Cognitive Assessment (MoCA, Ziad Nasreddine, 1966): is a screening instrument for cognitive impairment assessing visuospatial, naming, memory, attention, language, abstraction and orientation, with a total score of 30 (cut-off <26) (20),(21),(22). All the scales were free. Therapeutic regime- the drug and doses- was also analysed as per the advice of consultants (MD Psychiatry) using PANSS and M-BPRS. Patients were prescribed Haloperidol (one EOS patient, 10 mg), Trifluoperazine (one EOS, 4 LOS, 5-10 mg), Olanzapine (2 EOS, 4 LOS, 10-20 mg), Risperidone (22 EOS, 16 LOS, 4-8 mg) and Clozapine (1 EOS, 200 mg).

Statistical Analysis

Statistical analysis was done using International Business Management (IBM) Statistical Package for Social Sciences (SPSS) statistics for windows version 21. 0 (IBM corp. Armonk, NY). The parametric data were presented in mean, standard deviation, percentages, and p-values. Continuous variables were compared using student’s t-test, while discrete variables were compared using Chi-square test and non parametric tests (Mann Whitney U test). The entire statistical test was two-sided, and level for statistical significance was 0.05.

Results

A total of 100 patients suffering from schizophrenia were thoroughly screened. Out of these, 60 schizophrenic patients were selected by purposive sampling method, 30 patients in each early-onset and late-onset schizophrenia group who fulfilled inclusion criteria. Further nine patients, three in EOS group and six in late-onset schizophrenia group could not complete this study due to severity of physical/psychiatric disorder needing emergency treatment referred to higher centre. Remaining 21 patients, 27 from EOS group and 24 from late-onset schizophrenia group formed the sample of study and their baseline assessment was done following which another assessment was done after four weeks.

The demographic characteristics and psychiatric co-morbidity status of the two groups are shown in (Table/Fig 1). As expected, mean age ( EOS 30.11±6.96 years and LOS 57.66±10.14 years), mean age of onset (EOS 22.05±5.8 years and LOS 55.54±10.23 years) and mean duration of illness (EOS 7.98±5.19 and LOS 2.12±1.93 years) of both the groups was significantly varied. Also subjects of EOS were educated upto middle school (11 (40.8%) whereas that of LOS were illiterate (n=14, 58.3). Subjects of both groups were mostly married (n=14 (51.9%) for EOS and n=16 (66.7%) for LOS), belonging to upper lower socio-economic class (n=14 (51.8%) EOS, n=16 (66.7%) LOS), residing in rural locality (n=19 (70.4%) EOS and n=20 (91.7%) LOS) and unemployed (n=19 (70.4%) EOS, n=20 (83.4%) LOS). Family history of psychiatric illness was uncommon in both groups, whereas n=6 (22.22%) for EOS and n=6 (25%) for LOS, precipitating factors were noted as n=2 (7.40%) in EOS and n=2 (29.16%) in LOS, 8% of patients had another co-morbid psychiatric condition in EOS as well as LOS.

Baseline and four weeks assessment of PANSS and MoCA is given in (Table/Fig 2). PANSS composite scale score at baseline and 4 weeks were significantly different for EOS and LOS, however there was no change in score for LOS at 4 weeks. PANSS positive scale score and PANSS general psychopathology scale score of EOS and LOS was significantly different at baseline and 4 weeks, however, PANSS negative scale score for EOS and LOS was not different significantly at baseline.

The PANSS individual domain score (Table/Fig 3) at baseline and 4 weeks within EOS changed significantly in conceptual disorganisation, hallucination, suspiciousness, grandiosity, blunted affect, emotional withdrawal, rapport, passive apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, mannerisms, motor retardation, unusual thought content, lack of judgement and insight, disturbance of volition, pre-occupation and active social avoidance. Whereas PANSS individual domain score at baseline and 4 weeks in late-onset schizophrenia changed significantly in delusion, hallucination, suspiciousness, blunted affect, emotional withdrawal, passive apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotype, somatic concern, anxiety, lack of judgement and insight, disturbance in volition, preoccupation and active social avoidance.

(Table/Fig 4),(Table/Fig 5),(Table/Fig 6) show response in PANSS scale parameters, antipsychotics prescribed and gender relationship with response. Response at 4 weeks is defined as 50% reduction in baseline PANSS scale score. Significantly more response was noted in EOS PANSS positive scale as compared to LOS (Table/Fig 4), whereas, no response was seen for PANSS negative and general psychopathology scale. In (Table/Fig 5), response was seen in 10 patients in EOS group (one patient with haloperidol, nine patients with risperidone) and 2 patients in LOS group (with risperidone). Furthermore, out of 28 females and 23 males, 6 females and males showed response (Table/Fig 6).

Discussion

Earlier authors regarded early and late-onset forms of schizophrenia as the same disorder, concentrating on the similarities and ignoring the differences between them. Although, there are undoubted similarities between the symptoms of early and late-onset schizophrenia, there are also clear differences. Late-onset schizophrenia is similar, but not identical to the early-onset illness, atleast in its phenotypic expression. Socio-economic variables like mean age (30.11±6.96 years for early-onset and 57.66±10.14 years for late-onset); gender distribution (70.3% males in EOS and 83.3% females in LOS); socio-economic distribution (upper lower); marital status; education; and residence (majority rural in both groups) were similar to Jeste DV et al., Roth M, Van Os et al., Sham PC et al., Lehman SW, Girard C and Simard M, Croudace TJ et al., clinical profile variables as age of onset (22.05±5.8 years for EOS; 55.54±10.23 years for LOS), duration of illness (7.98±5.19 years for EOS; 2.12±1.93 years for LOS), psychiatric (7.4% in EOS; 8.3% in LOS) co-morbidity, family history of psychiatric illness (11.1% in EOS and 8.3% in LOS) and precipitating factors (22.2% in EOS and 25% in LOS) corresponds with previous studies (23),(24),(25),(26),(27),(28),(29). As would be expected, age of patients, age of onset of illness and duration of illness were significantly different in both groups, however, in addition to the gender, marital status and education were also distinct in both schizophrenia groups, which may be attributable to the region itself and the age of onset of illness. In PANSS scale, delusions and hallucinations are the common symptoms and negative symptoms are less common, in accordance with other published reports by C. Huang and Zhang YL and X. Huang et al. (30),(31). The mean positive scale score of 19.77 was comparable with previous studies Girard C and Simard M (28). Late age of onset has been associated with paranoid-hallucinatory symptoms and paranoid schizophrenia in subtypes had reported that negative symptoms and thought disorder occurred to a significantly lesser degree in the LOS group. The relatively same MoCA score at baseline and 4 weeks in both groups point towards the stability of cognitive impairment over time (32),(33). Both LOS (22 out of 24, 91.7%) and EOS (22 out of 27, 81.5%) patients had moderate to severe cognitive impairment in MoCA scale which coincides with available data, which may be due to sensitivity of MoCA scale and the severity of patients reaching tertiary centres (34). The slightly higher cognitive impairment in LOS group may be due to slightly higher illiteracy in this group.

In EOS group, response (PANSS positive scale score at 4 weeks ≤50% of PANSS positive scale score at baseline) was seen in 10 out of 27, 37% of patients, meanwhile it was seen in 2 out of 24, 8.33% of patients of LOS group. There was no response in PANSS negative scale and general psychopathology scale after 4 weeks follow-up in both groups. Response was seen with Risperidone in nine patients of EOS group and two patients of LOS group. In EOS group, no response was seen with Trifluoperazine, olanzapine, clozapine, whereas in LOS group, no response was seen with Trifluoperazine and olanzapine, which is on par with our initial hypothesis. Risperidone was the highest prescribed antipsychotic in both EOS and LOS group. The confounding factor here could be due to inappropriate and in equivalent dosing, poor drug compliance and risperidone was the highest prescribed antipsychotic. A Cochrane Review conducted in 2012 regarding the use of antipsychotics in LOS found that symptoms decreased in both treatment arms on the Brief Psychiatric Rating Scale (31),(35). In short, there was not enough trial-based evidence upon which to base guidelines for use of antipsychotics in LOS. Jeste DV et al., (2003) concluded that stable elderly patients with chronic schizophrenia receiving appropriate doses of risperidone or olanzapine over eight-week period experienced significant reductions in the severity of psychotic and extrapyramidal symptoms, with a relatively low risk of side-effects (36). In comparison to the present study, only risperidone showed significant improvement. This may be due to Risperidone is the highest prescribed antipsychotic in both early and late-onset schizophrenia group in the present study.

A short-term outcome study of broad psychotic disorders would be necessary to describe potential similarities and differences in psychopathology between early and late-onset schizophrenia more precisely. Information regarding elderly LOS is limited, and further large scale longitudinal studies encompassing other community subsets are required. Further longitudinal studies are needed for improving understanding of the cause-effect relationship. The assessment did not include imaging or biological factors; these factors should be included in future studies for analysis. Further research into the epidemiology and phenomenology of such patients should seek to integrate findings with other factors pertaining to the etiology of late-onset schizophrenia. Further systematic research into its epidemiology, phenomenology, and genetics, other biological and psychosocial issues, and course and outcome are necessary for a better understanding of this condition.

Limitation(s)

Major limitation of this study is the sample size, which was not large and constituted only of institutionalised patients, thus hindering the generalisability. Also there was no blinding in this study as compared to other studies. Since subjects with diagnosis on last day of index hospitalisation were included, there is a possibility that some psychotic patients who may receive diagnosis of schizophrenia in future were left out.

Conclusion

It was concluded that schizophrenia can manifest for the first time in late life and manifestations of stringently defined schizophrenia is by no means confined to onset at younger ages. Delusions and hallucinations are the common symptoms and negative symptoms are less common, in accordance with other published reports. This study has also revealed the other most consistent finding that women were more prevalent than men in late-onset schizophrenia. The authors in the present study found that both LOS and EOS patients had cognitive and functioning impairment with poor global outcomes. An association of LOS with lower educational levels was observed in this study. There is only response in positive symptoms after 4 weeks of prescribed antipsychotic treatment in both EOS and LOS group, significantly more in EOS. Late-onset schizophrenia is largely ignored and understudied as evidenced by scarcity of literature on the subject. One reason for this is a widespread failure to recognise it as a condition apart from EOS which, as such, deserves an investigative attention. The current study has shown that it is possible on clinical grounds to recognise separate early and late-onset schizophrenia syndromes.

DOI and Others

DOI: 10.7860/JCDR/2022/57582.17318

Date of Submission: May 05, 2022
Date of Peer Review: Jun 23, 2022
Date of Acceptance: Nov 26, 2022
Date of Publishing: Dec 01, 2022

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA

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