When one looks at the history of psychiatric treatments, prior to availability of electroconvulsive therapy (ECT), measures like magic, restraints, blood letting, emetics, purgatives, surgical operations on various organs, removal of foci of infections, vaccines and endocrines were tried as treatment options for schizophrenia. Therapies like insulin coma and electroconvulsive therapy became available. However, the era of pharmacotherapy for treatment of schizophrenia started with use of chlorpromazine by Delay and Deniker for the treatment of patients suffering from schizophrenia in early 1950’s. Over the next half century, a large number of drugs have been evaluated and marketed as antipsychotics. This class of drugs also helped in understanding the neurobiology of schizophrenia to some extent. This class of drug has also changed the attitude of the clinicians towards the expected outcome of the disorder.
India, as a country was not isolated from all these developments. Over the years many classes of antipsychotics have become available in India, some of which have stood the test of time and are still in use and some are no more marketed or are no more favorite of the clinicians. Research focusing on the usefulness of psychotics in India has more or less followed the trends in the West; however, some of the newer antipsychotic drugs which are currently marketed have not been evaluated as thoroughly as others. The pharmaceutical industry and the policy of the government have ensured that these medications are available at a reasonable price.
This review focuses on research done on various anti psychotics in India. For this a thorough internet search was done using key words like India, antipsychotics, name of each antipsychotic, efficacy, effectiveness, usefulness, tolerability, side effects, metabolic syndrome, weight gain, prescription, cost in various combinations. Various search engines like PUBMED, GOOGLE SCHOLAR, SCIENCEDIRECT, SEARCH MEDICA, SCOPUS, and MEDKNOW were used. In addition, a through search of all the issues of Indian Journal of Psychiatry available online was done. Hand search of some of the missing issues was also attempted and this yielded a few more articles. We have excluded review articles which we felt did not reflect the Indian scenario to a large extent or did not cover the available Indian data. Data from the animal studies that originated in the form of case reports and studies published only as abstract have not been included.
EFFICACY OF ANTIPSYCHOTICS IN SCHIZOPHRENIA
Efficacy of first generation antipsychotics in schizophrenia [Table 1]
Twenty eight studies which have evaluated the efficacy of first generation oral antipsychotics in schizophrenia have been published.[2–29] Of these, most have been open trials, some have been double blind randomized controlled trials and only a few have compared active drug with placebo. Some have also followed the cross over design with intermediate drug free period. Some of the initial trials included subjects who had not responded to previous pharmacological or somatic treatment and were suffering from chronic schizophrenia. Further, some studies have included treatment refractory subjects and others have recruited only those subjects who responded to some medication in the past. The sample size has varied from 15 to 145 subjects and the duration of trials have varied from eight days to six months, but most have evaluated the subjects in 4-12 weeks. Most of the trials included subjects with acute symptoms, however, one trial evaluated the efficacy of penfluridol and haloperidol in the maintenance phase and another included subjects who, on baseline, had shown at least 50% response on BPRS to the previous antipsychotic medication.
Except for some of the trials in the 1960s and early 1970s, the efficacy and side effects were measured on some rating scales. All these trials have not used the dropouts in their final analysis of data. Data from all these trials can be summarized as: Typical antipsychotics are useful for treatment of schizophrenia, typical antipsychotics are more efficacious than placebo in the treatment of schizophrenia, improvement is seen more in paranoid and catatonic symptoms, aggression and less so in depressive symptoms; addition of trihexyphenidyl doesn’t reduce the efficacy of antipsychotic like trifluperazine and extrapyramidal symptoms are common with typical antipsychotics.
Efficacy of injectable depot first generation antipsychotics in schizophrenia [Table 2]
Nine trials have evaluated the efficacy of depot antipsychotics in schizophrenia.[30–38] Some of these trials have just focused on short term outcome (2-4 weeks), whereas others have evaluated the outcome after six months. One trial followed up the subjects for 1-3 years. In most of these trials subjects included were those who were non-complaint to oral medications and had frequent relapse. All these were open label and did not use a comparator group, except for the trial by Bagadia et al. that compared subjects on fluphenazine decanoate with subjects who has been receiving either chlorpromazine or trifluperazine. All these studies have shown that depot antipsychotics are useful in the management of schizophrenia in acute phases and also for maintenance treatment.
Efficacy studies of first generation antipsychotics vs. electroconvulsive therapy/electroconvulsive therapy and first generation antipsychotics in schizophrenia [Table 3]
Thirteen studies have compared typical antipsychotics with either electroconvulsive therapy (ECT) alone or a combination of ECT and typical antipsychotic medication.[139–50] All studies have specified the diagnosis as schizophrenia, except for one study, in which the diagnosis was mentioned as functional psychosis. A common theme which emerges from these studies is that typical antipsychotic, alone or when used in combination with ECT, produces similar response rate in short term, but addition of ECT leads to a faster response. The only study which evaluated the efficacy of ECT and chlorpromazine in treatment resistant schizophrenia (TRS) showed that augmentation with ECT in TRS may be a worthwhile option.
Efficacy of centbutindole [Table 4]
Centbutindole was developed by Central Drug Research Institute, Lucknow; it has been evaluated in four trials and has been compared with trifluperazine, haloperidol and risperidone (see Table 5 for this trial). These studies have shown that centbutindole is as efficacious as haloperidol, trifluperazine and risperidone in the treatment of schizophrenia.
Efficacy studies of second generation antipsychotics in schizophrenia [Table 5]
Twenty studies have been published on evaluation of the efficacy/effectiveness of second generation antipsychotics in schizophrenia.[54–73] Of these trials, 11 have reported the efficacy of risperidone, five of clozapine, two of olanzapine, two of aripiprazole and one of quetiapine. Some of these studies have also evaluated different doses of the same medications and some others have evaluated the dosing schedule. All these trials have included subjects diagnosed as schizophrenia on the basis of DSM-IV or ICD-10 except for Agashe et al. who used DSM-IIIR criteria. All these trials have used standard instruments to assess the efficacy and side effects. The sample size has varied from 30 to 606 and the duration of these trials have been six weeks to four months except for one trial which evaluated the outcome on risperidone at one year and two studies, which followed up subjects on clozapine for 20 months and three years respectively. All the studies on risperidone have shown that it is efficacious in short term. Studies which have compared risperidone with other antipsychotic have shown it to be more efficacious than quetiapine but as efficacious as haloperidol and centbutindole. Agarwal and Chadda demonstrated that there was no difference in efficacy of once daily dose versus twice daily dose of risperidone. The study which followed up the subjects on risperidone for one year showed that compared to haloperidol, more subjects on risperidone had better social functioning, productivity and education and significantly fewer patients had suicidal ideation or attempts and needed rehospitalization. Srivastava et al. showed that half of the schizophrenia subjects in India require 3-4 mg/day of risperidone and another one-third improve with dose ranging from 1-2 mg/ day. All the studies which have evaluated clozapine have done so in TRS cases and have reported it to be useful in both short and long term. In the study by Avasthi et al. olanzapine was found to be as efficacious as haloperidol on PANSS. Additionally olanzapine was found to be better than haloperidol in reducing associated depressive and anxiety symptoms. Sarin et al. reported no difference in efficacy of 10 and 15 mg/day of aripiprazole.
Efficacy of antipsychotics in other disorders: mania [Table 6]
Some of the older studies included a few subjects with mania. Three studies in the early 60s included very few subjects in the open label design studies and reported efficacy of haloperidol, thioridazine and thioproperazine in the treatment of mania. One study included only one case of treatment refractory mania and showed that oral fluphenazine was not useful in such subjects. Another study evaluated the efficacy of zuclopenthixol in management of 25 cases of mania. This study did not specifically report the efficacy of zuclopenthixol in mania, but irrespective of the diagnosis the reported outcome suggests that zuclopenthixol for eight weeks was useful.
However, in the recent trials, atypical antipsychotics have been evaluated in large samples in double blind placebo control trials and the outcomes have been measured using standard instruments. In the study by Khanna et al. risperidone was found to be significantly better than placebo at weeks 1 and 2 and 3 (total YMRS: P < 0.01). Another multicentric trial, which included subjects from India too, showed that both risperidone and haloperidol were better than placebo; however, there was no difference in the efficacy of risperidone and haloperidol. At three weeks, more patients were treatment responders (>50% reduction in YMRS total scores) among those treated with risperidone (48%) or haloperidol (47%) than placebo (33%). The difference between risperidone and placebo was significant (P < 0.01). At 12 weeks, the response rate was maintained in almost all subjects who responded at three weeks and additionally more than 80% of the subjects who did not respond (reduction of >50% in the YMRS total score) to risperidone or haloperidol at three weeks but continued the medications responded at 12 weeks.
Acute psychosis [Table 7]
Four studies have reported the efficacy of antipsychotics in the management of acute psychosis, of which three have specified that the trials included subjects with acute and transient psychosis, while another trial mentioned the diagnostic category only as acute psychosis. Trial by Agarwal and Sitholey involved children and adolescents presenting with acute and transient psychosis and is discussed later. These studies suggest that thioproperazine is better than chlorpromazine and there is no difference in short term efficacy of risperidone and haloperidol in acute and transient psychosis. As mentioned earlier Fernandes et al. did not specifically report the outcome in acute and transient psychosis, however, irrespective of the diagnosis the reported outcome suggests that zuclopenthixol for eight weeks was useful.
Studies in 1970s and 1980s evaluated the efficacy of low dose haloperidol, flupenthixol, trifluperidol, pimozide, prochlorperazine, trifluperazine in various anxiety states and reported these to be efficacious. The study which used pimozide compared it with chlordiazepoxide and reported it to be useful, but inferior to chlordiazepoxide. The study which compared trifluperazine and chlordiazepoxide combination with prochlorperazine reported the latter to be better.
Agitation and violence
Two studies have evaluated the role of antipsychotic in violent and agitated subjects attending the psychiatry emergency settings. In a randomized controlled trial, Alexander et al. compared the efficacy of injectable lorazepam and a combination of injectable haloperidol and promethazine and reported that after four hours of the injection, 96% of the subjects in both the groups were tranquil or asleep. However, in terms of being asleep, 76% of the subjects given haloperidol-promethazine were asleep compared to 45% of subjects in the lorazepam group. The haloperidol-promethazine combination also produced a faster onset of tranquillization/sedation and more clinical improvement over the first 2 h. Neither intervention differed significantly in the need for additional intervention or physical restraints, subjects absconding, or adverse effects. In another randomized study from the same centre, Raveendran et al. compared the efficacy of intramuscular olanzapine with intramuscular haloperidol plus promethazine in 300 subjects and reported that both treatments led to similar proportions of subjects being tranquilized or asleep at 15 minutes (olanzapine-87%, haloperidol plus promethazine-91%) and 240 minutes (olanzapine-96% and haloperidol plus promethazine-97%). However, compared to those given haloperidol plus promethazine, more subjects in the olanzapine group required additional drugs over four hours (21% vs. 43%). Adverse effects were uncommon with both treatments.
Only a small case series of seven cases reported that risperidone is effective in the management of delirium and it is well tolerated by these subjects.
Good response to antipsychotics like trifluperazine, haloperidol and chlorpromazine was reported in cases of delusional parasitosis. In their study on delusional disorder, Grover et al. found that best response was seen with risperidone, followed closely by pimozide. Of the 20 subjects treated with risperidone, six were considered to have good response (>75% reduction in symptoms) and nine were considered to have partial response (>25 but <75% reduction in symptoms). Of the 18 subjects treated with pimozide, four qualified for good response and six as partial responders.
Use of Antipsychotic in Children and Adolescents [Table 8]
Seven studies have evaluated the efficacy of various antipsychotics in childhood disorders or childhood/adolescent onset disorders. Studies done in 1960s and early 70s evaluated the role of antipsychotics primarily in the behavioral problems in children with epilepsy/epilepsy and mental retardation and have shown that trifluperazine, prothipendyl and trifluperidol are useful but fluphenazine is ineffective. One small study evaluated the usefulness of clozapine in childhood onset schizophrenia. A study which evaluated the role of risperidone in autism showed promising results and another study demonstrated the efficacy of olanzapine in childhood/adolescent onset acute and transient psychosis. However, the studies which used olanzapine and risperidone showed that these drugs lead to reasonable weight gain, which may be cause of concern.
RESEARCH ON OTHER TREATMENT RELATED ISSUES
With increasing interest in the role of genetic factors in treatment response and side effects of medications, studies from India have tried to address the genetic links of tardive dyskinesia, treatment response and severity of psychopathology.[93–96] However, the findings are preliminary and inconclusive. Tiwari et al. evaluated the role of six single nucleotide polymorphisms (SNP) in tardive dyskinesia and showed that CYP1A2 1545 C > T SNP was associated with TD (P = 0.03) and schizophrenia (P = 0.04), but the association was rendered insignificant after corrections for multiple comparisons. Vijayan et al.(2007) studied various alleles, genotypes, haplotypes and their linkage disequilibrium and observed that H313HTT genotype was associated with schizophrenia and TaqIB1B1 genotype was significantly associated with higher psychopathology score. Subjects with H313HCC, TaqIA2A2 and Taq1D1D1 had higher mean improvement scores. Distinct shift in the linkage disequilibrium pattern of responder and non responder group was observed. Thomas et al. reported that average olanzapine dose, baseline weight and dopamine receptor D-4 (DRD4-120 bp) duplication marker have significant association with the efficacy index. Gupta et al. reported significant allelic associations of two SNPs (rs4633 and rs4680) with drug response.
Predictors of Treatment Response
A study reported that subjects, who showed initial dysphoric response to a test dose of neuroleptic, later respond poorly to the neuroleptics.
A few studies have evaluated the antipsychotic prescription patterns from India. In one of the early studies, Khanna et al. evaluated the psychotropics drug prescription pattern in chronic long stay patients at Ranchi and compared the prescription trends in 1984 and 1988. Most of the patients whose prescriptions were reviewed were suffering from schizophrenia. More than one antipsychotic medication was prescribed to 13% in 1984, which fell down to 7% in 1988. Further it was seen that very few patients received anticholinergic agents and the use of benzodiazepines increased over the years (4% in 1984 and 10% in 1988), which authors attributed to development of distressing tardive dyskinesias over the years. In an evaluation of prescriptions at discharge of patients with schizophrenia, Padmini Devi et al. reported that risperidone was the most commonly prescribed antipsychotic (56.17%), followed by olanzapine (21.34%) and quetiapine (3.93%). Typical antipsychotics were used only in 15.73% of cases and polypharmacy (concurrent use of more than 1 antipsychotic) was seen in 9% of cases. In another study from Jammu, Shanwey et al. evaluated the prescription of 270 outpatients, and reported that fixed dose formulation of trifluperazine, chlorpromazine and trihexyphenidyl (parkinforte) was used in 45.4% of cases followed by chlorpromazine[36.3%] and quetiapine [34.5%]. The authors also found that typical antipsychotics were used in 82.72% of cases and polypharmacy was seen in 72.72% of cases. Dutta et al. evaluated the prescription patterns in 118 stable schizophrenia subjects and reported that on an average 2.8 medications were prescribed to each subject and olanzapine was the most commonly prescribed antipsychotic followed by haloperidol and risperidone. About half of the subjects were receiving more than one antipsychotic. All these findings suggest that antipsychotic prescriptions vary from centre to centre and possibly have changed over the years.
In a recently conducted survey, Grover and Avasthi found that the three most commonly prescribed antipsychotics by Indian psychiatrists were risperidone, olanzapine and haloperidol. Typical antipsychotics comprise 25.15% of all prescriptions and in about 22.36% of cases the psychiatrists were using more than one antipsychotic in the same patient. Another survey specifically assessed the prescribing practices of clozapine; only 28% of psychiatrists reported that their prescription of clozapine was guided by their knowledge about the efficacy of clozapine. Majority of the psychiatrists opined that clozapine leads to symptom reduction to the extent of 40 to 70%, and the average dose required for stabilization was between 75 to 300 mg/day. Only 16% of psychiatrists preferred to combine clozapine with other antipsychotics. In terms of blood monitoring, 80% of the psychiatrists monitored the blood counts weekly in the first month of therapy and then once monthly for next 6 months and further monitoring was done as per the need.
Treatment continuation, compliance and attitude towards treatment
Khanna et al. reported that 31% of the subjects with schizophrenia do not keep their appointment for detail evaluation after initial evaluation in the walk-in clinic. The authors also reported that 32% of the subjects stop attending the clinic after initial detailed workup and diagnostic clarification. In another study from the same center, Kulhara et al. reported that 25% of schizophrenia subjects do not come for follow-up after six months of detailed workup and diagnostic clarification and 23% of subjects with schizophrenia don’t seek any medical help in next five years. Murthy et al. studied a mixed group of patients (which included subjects of psychosis also) and reported that duration of illness more than six months, residence at a distance of more than 50 kilometers from the hospital and psychiatric diagnosis other than functional psychosis favored treatment discontinuation. Ponnudurai et al. evaluated the treatment adherence in 111 cases of psychotic illness (mostly schizophrenia) by Ferric Chloride reagent test to look for excretion of phenothiazine in urine and reported non-adherence in 19% of subjects. In another interesting study Srinivasan and Thara reported that history of noncompliance with oral medication was seen in about 58% of patients during the course of their illness and half of these subjects were given oral medications at least once without their knowledge by the family members under the psychiatrist’s advice. It was seen that spurious administration of antipsychotic leads to reduction in symptoms in 91% of subjects given medications in this way and helps to convince the patient to take oral medications subsequently. Half of the caregivers who participated in the study felt that spurious administration of antipsychotic was the right action under the circumstances. In a recent study, Baby et al. reported rates of non-compliance with medication to be 38.7% in subjects with schizophrenia. The authors also reported that a majority of the patients and family members had a positive attitude towards medication and treatment. Further, family members are able to identify the compliance status of the patients and the reasons for the noncompliance better than the patients. The factors which had significant influence on the medication compliance included perceived daily benefit from medication, positive relationship with the psychiatrist, pressure from the family and health system and positive family belief towards illness and treatment. The significant reasons for noncompliance are no perceived daily benefit from medications, difficulty in gaining access to treatment and medications, financial obstacles, embarrassment or stigma related to treatment and medications and medicines currently not perceived as necessary. Besides attitude, other factors which are significantly associated with noncompliance include lower educational status, rural area of stay, adjustment difficulty with family and spouse, previous history of non-compliance, poor insight into illness, higher positive PANSS score. Past history of hospitalization was associated with better compliance with medications.
Impact of antipsychotics on disability
A recently published study, which compared three groups of community dwelling subjects with schizophrenia, showed that mean disability scores remain virtually unchanged in those who remained untreated, but showed a significant decline (indicating decrement in disability) in those who continued to receive antipsychotics and in those in whom antipsychotic treatment was initiated. The proportion of patients classified as ‘disabled’ declined significantly in the treated group, but remained the same in the untreated group.
A few studies have evaluated the cost of antipsychotics per se and cost of management of schizophrenia. Girish et al. found that antipsychotic drugs are affordable and comparable to drug treatment costs of other physical illnesses. They found the monthly cost of treatment with chlorpromazine was Rs.55, an equivalent dose of trifluperazine amounted to Rs.25/month, risperidone Rs.60 and clozapine Rs.225 per month. They also concluded that although antipsychotic drugs are affordable, the other costs associated with treatment make them more expensive, like co-prescribed antiparkinsonian agents, antidepressants, anxiolytics etc. Sarma showed that cost of one outpatient visit was Rs.201 in which medications accounted for less than 10% of the total cost. Grover et al. found that the total annual cost of care of schizophrenia amounted to Rs.13687.38, which was similar to cost of treatment of diabetes mellitus. Money spent by patients on buying drugs constituted about 18% of the total costs. A study from Chennai showed that despite the cost of blood tests, the total cost of treatment with clozapine came down by nearly 25% compared to the cost before clozapine was started. In another study, Despande reported that the cost of medication to the hospital which provided free medications to subjects with schizophrenia was Rs.288-less than the cost of medications for bipolar disorders.
Research on Tolerability and Side Effects of Antipsychotic [Table 9]
Besides the efficacy or usefulness studies, some studies have specifically evaluated the side effects and tolerability issues with antipsychotics.[116–136] In one of the earliest studies, Sarada Menon and Ramachandran reported side effects of subjects who participated in two of their drug trials and had received either trifluperazine or trifluperidol. Other studies have evaluated the rates of skin pigmentation with phenothiazines, rise in prolactin levels with chlorpromazine and trifluperazine and changes in serum electrolytes. Studies have reported prevalence rate of akathesia (25-28%), tardive dyskinesia (5-25.5%) and dystonia (17%) in subjects receiving typical antipsychotic.[118121–123] Studies have also evaluated the incidence of neuroleptic malignant syndrome and extrapyramidal side effects with risperidone. Another study by Pandey et al. compared the rate of neuroleptic - induced acute dystonia and reported that there was no difference in vulnerability to develop dystonias in subjects with mania or schizophrenia. With recent interest in weight gain and metabolic syndrome, some of the studies have shown that patients receiving atypical antipsychotics (Olanzapine or risperidone) gain more weight compared to haloperidol and treatment with antipsychotic leads to disturbance in metabolic syndrome parameters[131–133] whereas others suggest contrary findings. Studies have also shown that use of typical antipsychotic leads to higher rates of sexual dysfunction and among the atypical antipsychotic sexual desire is more frequently impaired in subjects on risperidone and erectile dysfunction is more prevalent in subjects on olanzapine.
CONCLUSION AND FUTURE DIRECTIONS
Reasonably good amount of data on the efficacy of antipsychotics in schizophrenia is available from India. In addition, studies also suggest usefulness of antipsychotics in mania, acute and transient psychosis, delusional disorders and agitation and violence. Older studies also suggest that typical antipsychotics have usefulness in anxiety states. Many of the recent studies followed double blind randomized controlled design and had a reasonable sample size. Further, many studies have been carried out at multiple sites throughout the country. To some extent, data is also available with regards to the tolerability of antipsychotics and it shows that extrapyramidal symptoms and NMS are more common with typical antipsychotics and weight gain is more common with antipsychotics like olanzapine and risperidone.
However, the major limitation of the research is that there are not many studies on the treatment of schizophrenia in elderly, in subjects with comorbid physical illnesses and in cases with comorbid substance abuse. Data on long term efficacy of antipsychotics is also meager. There is still a need to conduct long term comparative multicentric studies to evaluate the efficacy, effectiveness, tolerability and side effects of antipsychotics.
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Conflict of Interest: None declared.