Table 1.

Efficacy of first generation antipsychotics in schizophrenia

Authors	Duration (weeks)	Sample size/scale/design	Medication (s)	Dose (s) (mg)	Outcome	Side effects
Doongaji et al.[2]	6	N = 18; Open Trial	Prothi pendyl	Phase I- 120-240 Phase II- 160	2 out of 8 subjects in the psychosis group (who were administered drug im) showed significant improvement, 3 cases showed some improvement and 3 cases showed no improvement	The optimum dose of the drug ranged between 120 mg/day and 160 mg/day Doses above 160 mg/day caused more sideeffects, and dose reduction was needed in 4 cases Side-effects were increased if the drug was prescribed as single doses exceeding 40 mg 5/8 subjects who were administered dose im had significant fall in blood pressure
Sarada Menon[3]	8	N = 20; Catatonic Schiz DBPCT	PCPZ Vs. PBO	100	2 out of 10 subjects who received PCPZ were remarkably improved, 1 showed favorable improvement and 5 showed appreciable change in behavior. No change was observed in 2 subjects 1 case of periodic psychosis improved on PBO The earliest change in behavior in the PCPZ group was decrease of withdrawn behavior and it was observed by 4-5 weeks	Drug was discontinued in one subject because she became cold and clammy and she refused to take food Another patient developed hypotension, cold extremities, EPS and developed excitement There was no change in blood counts and there was no evidence of hepatic damage
Damania and Masani[4]	8 days-4months	N = 20; Open label Schiz.	TRZ	30-300	18 out of 20 subjects with Schiz improved, of which 1 was considered as cured	Drowsiness and giddiness No serious S/E were noted
Kothari[5]	4	N = 15; (12 Schiz) Open label, Treatment Refractory	FFP oral	2.5-20	1 patient showed marked improvement, 2 subjects with catatonic stupor showed mild improve ment, in 4 patient hyperactivity worsened and they became violent, 8 subjects showed no change	4 subjects became extremely disturbed and violent 5 subjects showed EPS (excessive salivation, rigidity, and tremor but these were mild)
Bhaskaran[6]	6	N = 35; Open label, Schiz.	TPZ	90	Of 28 Schiz subjects- 3 subjects recovered, 11 subjects improved markedly, 8 improved and 6 remain unchanged	The Akinetic-hypertonic syndrome was noticed in 25 cases Hyperkineto-Hypertonic Syndrome was noticed in 16 subjects Both these syndromes improved with antiparkinsonian medications, ankinetic type improved more than hyperkineto- hypertonic type No serious CVs. adverse effects No evidence of significant neutropenia or hepatic damage
Thomas and Narayanan[7]	12	N = 10; RCT, Koh’s block design, pass along test, MMPI, TAT	TFP Vs. UCPZ	TFP-5-15 UCPZ-200	Of the 6 subjects receiving TFP, 1 showed marked improvement, 3 showed moderate improvement, 1 showed slight improvement and 1 died after 7 weeks of trial, (cause of death not known, had features s/o vitamin B deficiency) Of the UCPZ group, 2 showed moderate level of improvement, 1 showed slight improvement and 1 showed no improvement A trend of improvement in intelligence, however, the difference was not significant between the 2 groups	1 out of 6 TFP pt had S/E- masked faces, rigidity, drooling of saliva, improvement in S/E with decrease in dose and adding THF UCPZ group- giddiness Periodic blood and urinary check-ups in both groups showed no significant changes
Jetley[8]	6	N = 16; (Schiz-10; Mania-6), Open label	HPL	Mania–1.5-4.5 Schiz- 6-9	All subjects with schizophrenia showed improvement in sphere of over activity and verbal aggression towards others in environment and also in sphere of social contacts. In 4 subjects the paranoid delusions melted away and there was improvement in inter-personal relationship	Subjects developed EPS which improved with THF 2 subjects developed intractable motor restlessness which responded to phenergan in one
Dube and Mathur[9]	4	N = 35; Open label	TRZ	300	10 subjects showed good improvement, 5 showed moderate improvement, 8 slight improvement and 12 did not show any improvement Catatonic excitement responded best and most swiftly Symptoms of a better response included-irritability, excitability and abusiveness, overactivity spontaneous talks, mutterings and incoherency Symptoms corresponding to the fundamental symptoms of schizophrenia (thought disorder, thought block, emotional blunting, odd mannerisms, carelessness, poor judgment and tendency to roam aimlessly) responded least Better results were seen in early illnesses and lower age group Females showed less improvement than males, but the difference was not significant Patient with mental sub normality showed no improvement	S/E- Weight gain, tachycardia, drowsiness, lability of pulse, hypotension, stuffiness of nose, giddiness, dryness of mouth, stuffiness of tongue, excessive salivation, loss of appetite, vomiting, metallic taste, weakness, subnormal temperature, feeling of intoxication.
Narayan et al.[10]	20	N = 20; Comparative trial	PCPZ Vs. CPZ	PCPZ-100 CPZ-200	In the PCPZ group 5 subjects were rated as much improved, 3 as moderately improved, 1 as slightly improved and 1 remained as before In the CPZ group, 3 subjects were rated as much improved, 4 as moderately improved, 1 slightly improved and 2 had no change in their status In majority of the cases, definite changes were observed between the 5th and 6th week after starting of the drugs, the earliest sign was the shedding of withdrawal, and they were more communicable and manageable PCPZ seemed to increase drive and affect in chronic schizophrenics, whereas CPZ was found to be about 20% less effective	3 of the 10 PCPZ subjects developed EPS with in first week and required treatment with phenergan No hematological S/E or liver dysfunction
Teja[11]	14 months	N = 25 Schiz Open label PSSR	Thiopro perazine	5-25	6 subjects recovered, 5 markedly improved, 3 improved and 11 maintained same. 1 patient who had inadequate trial showed marked improvement Best results were seen in paranoid and catatonic groups There was no evidence of any relation between therapeutic response and occurrence of S/E	No abnormality was detected on hematological, urinalysis or liver function test S/E noted were weakness, tremors, rigidity, agitation, anxiety, visual accommodation difficulty, insomnia, headache, depression, masseter spasm, tachycardia, sialorrhoea, petrified dejected look, opisthotonus, parkinsonian facies, excessive sweating, transient urinary retention, elation, speech difficulty, facial spasm, anorexia, indifference, burning sensation, dizziness
Sarada Menon and Haneef Badsha[12]	1 year	N = 30 Chronic Schiz, Rating on Behavior chart, DBRCT cross over design	Thiothixene vs. TFP vs. PBO	Thioth ixene - 15-30 TFP-15-30	In controlling delusion and hallucinations, thiothixene was better than TFP In controlling over talkativeness and occupational activity TFP was better than thiothixene On analysis of all symptoms, it was found that 44.2% of improvement was due to thiothixene, 35.3% was due to TFP and 20.5% was due to PBO 27 subjects showed improvement with thiothixene, 24 subjects showed improvement with TFP and 8 with PBO out of 30 subjects	EPS, autonomic symptoms, and GI S/E were noted No S/E was serious enough to warrant discontinue No abnormality was noted on hematological investigations, LFT, RFT and urine analysis
Kishore et al.13]	3 months; After 3 months, each patient was put on CPZ 300 mg/day and followed for 3 months	N = 60 Chronic Schiz, PSSR DBCT	Thiothixene vs. triflupro mazine vs. CPZ vs. TFP vs. PCPZ vs. Thiopro perazine	Thiot hixene-30 Triflupro mazine-150 CPZ-600 PCPZ-150 TFP-30 Thiopro perazine-30	Significant improvement was seen in 8 subjects on TFP, 7 on PCPZ, 5 each on thiothixene and thioproperazine and 4 each in CPZ and triflupromazine group Drugs have different degrees of improvement in various symptoms. In behavioral disturbances 80% subjects in PCPZ group showed improvement, 60 % each in TFP, thiothixene and thioproperazine, and 50% in both CPZ and triflupromazine group In thought disorder, 70% in PCPZ group, 40% in TFP, CPZ and thiothixene group, 30% in thioproperazine group and 20% in triflupromazine group In the affective symptoms, improvement was seen in 70% in PCPZ group and TFP group, 50% each in thiothixene, thioproperazine and triflupromazine group and 30% in the CPZ group In the symptoms of sleep, appetite and sexual disturbances, 100% improvement in PCPZ, TFP, CPZ and triflupromazine group and 75% in both thiothixene and triflupromazine	EPS (rigidity, tremors, akathisia, dystonia) CNS (giddiness, insomnia, feeling of weakness in limbs Autonomic (hypersalivation, constipation, urinary frequency) Endocrinological (gynecomastia) Toxic (jaundice, skin rash/Pruritus) All these drugs caused a fall in BP in 50-90% of the subjects
Bagadia et al.[14]	4	N = 145 Open label, Schiz	FFX	1.5-9	29 subjects dropped out before completion of 2 weeks of trial Out of 116 subjects who continued treatment for 2-4 weeks, 54 showed significant improvement (46.5%). Significant improvement was observed in 46.1% of the subjects in drive deficit group and in 26.8% of the subjects in non-drive deficit group. Significant improvement was highest in the catatonic group (12/18 i.e. 66.6%) 8/19 (42.1%) subjects of chronic type had significant improvement.	Drowsiness (commonest S/E), tremor, EPS, giddiness, generalized weakness, restlessness, dryness of month, constipation, nausea, increased appetite, excessive perspiration
Bagadia et al.[15]	4	N = 100 Open label	TFD	1-4	24 subjects dropped out before completion of 3 weeks of trial	EPS (Tremors, spasms and rigidity, oculogyric crisis, slurred speech), palpitations, chest-pain, dryness of mouth, constipation, drowsiness, fatigue, weakness, skin rash.
					50 out of 76 subjects (65.8%) (Who completed three or more weeks of treatment) showed significant improvement.
					Subjects with paranoid schizophrenia responded best
					None of the cases of schizoaffective and pseudoneurotic schizophrenia improved. In other types (simple, hebephrenic, chronic undifferentiated, acute undifferentiated and mixed type), the rate of improvement was on an average 61%.
					Subjects with illness duration less than 1 year showed maximum improvement.
Ramachandran and Sarada Menon[16]	6	N = 50 Consecutive sampling; Schiz DBRCT, QPSS, WBRS	TFD Vs. PBO	15	88% of the patients on TFD showed marked improvement and 8% showed moderate improvement compared to 8% and 23% respectively on PBO and the difference was statistically significant.	EPS
					Patients on TFD showed significantly better improvement in thought disorder, emotional disturbances, catatonic symptoms, ideas of reference, persecutory and grandiose delusion and auditory, visual, olfactory, gustatory and tactile hallucination.	No changes in laboratory investigations
					Patients on TFD showed significantly better improvement in thought disorder, emotional disturbances, catatonic symptoms, ideas of reference, persecutory and grandiose delusion and auditory, visual, olfactory, gustatory and tactile hallucination.
					Improvement in reality orientation, judgment, and insight were also seen.
Vyas and Bapana[17]	6	N = 40	Go 3315	300-600	65% of the subjects improved while 35% did not show improvement.	S/E were not reported by the authors
					Symptoms of insomnia, automatic obedience, anxiety, passivity feelings, stereotype behavior, mannerism, suspiciousness completely recovered.
					Symptoms of excitement, negativism, impulsive behavior, inappropriate behavior, paranoid delusion, apathy and other delusions showed marked improvement.
					Lack of volition and incoherence were minimally improved and there was no improvement in depersonalization.
Kishore et al.[18]	3 months	N = 60 Chronic Schizophrenia, PSSR, DBCT	TFD Vs PCPZ Vs Thioxanthene	TFD-6 PCPZ-150 Thioxanthene-30	All three drugs were effective for psychotic symptoms and symptoms in the domains of sensorium, behavior, thought and emotional disturbance.	S/E were maximum in case of TFD followed by thioxanthine and were least in the PCPZ group
					There was no significant difference between the three drugs in overall improvement in psychopathology and between PCPZ and thioxanthine in the subscales of sensorium, behavior, thought and emotions.
					However, in the subscale of sensorium, PCPZ was better than TFD, and both PCPZ and thioxanthine were better than TFD in the subscale of emotional disturbances.
					The dosages used in the present study are effective dosages in majority of the subjects.
Kishore and Dhillon[19]	3 months	N = 40 females Schiz, Open label, MSQ	PMZ	1-5	11 subjects showed slight improvement, 16 showed moderate improvement, 11 showedd good improvement, 1 patient had excellent improvement, and 1 patient was unchanged or slightly worse.	There was no abnormality on haematological parameters or urinalysis
					The psychotic symptoms were reduced by 13.5%.	Mild EPS in form of tremors, rigidity, drooling nausea and vomiting, akathisia was seen.
					The ward bearing and behavior improved by 21.0%	Severe EPS occurred in 1 patient who had tremor, rigidity, akathisia and excessive salivation.
					Symptoms which improved considerably included emotional withdrawal, hostility, tension, anxiety and blunted affect.	1 subject developed somatic concern and 3 subjects had suspiciousness while on treatment.
					There was also appreciable improvement in disinterest in appearance, reluctance to work, social withdrawal, lack of leisure interests, and misbehavior at meals, this helped them to get engaged in work.
Sarada Menon et al.[20]	8	N = 40 Chronic Schiz, BPRS, QPSS Controlled cross over trial (8 weeks of drugs followed by 6 weeks of washout and then 8 weeks of other drug)	PMZ Vs. FFP	PMZ-8 FFP-10	It was observed that symptoms became worse while the subjects were on other medication and improved significantly while on PMZ or FFP.	On PMZ 1 patient developed EPS and 3 developed insomnia, the same was 4 patients and 1 patient respectively for FFP.
					On QPSS, improvement was noticed for patients on PMZ and FFP.
					Both PMZ and FFP were found to have a highly significant therapeutic effect.
Bagadia et al.[21]	12	N = 61; Open label, Treatment responsive Schiz.	PMZ	1-4	After the subjects were shifted to PMZ, 68% subjects maintained improvement, 26% had further improvement while 12% of the subjects worsened.	Oculogyric crisis, salivation, rigidity, tremors, restlessness No significant change was seen in hemogram, liver function tests, blood urea, blood sugar and urine routine examination
De Sousa and Nayani[22]	6	N = 50; Schiz Controlled trial	TFD vs. TFP	TFD-3 TFP-15	17 subjects showed significant improvement in the TFP group, while 15 in TFD group showed significant improvement TFD group more improvement in excitement and insomnia TFP had better control of delusions and hallucinations Both the drugs were equally efficacious in controlling concentration and irrelevant speech	Mild S/Es seen in both the groups: Drowsiness, constipation, blurring of vision, dryness of mouth, EPS (rigidity and tremors), difficulty in micturation, fatigue, rash TFD: Serious EPS (N = 2), skin rash (N = 1)
Mahal and Jana kiramaiah[23]	6 months	N = 62 Chronic Schiz, DBPCT cross over design, SMSQ	PMZ vs. PBO	2-4	In the first three month trial period there was greater improvement in the PMZ group as compared to the PBO group In the second three-month period there was no improvement in both the groups, rather psychotic symptoms and ward behavior worsened	EPS and sedation seen initially with PMZ
Channa basavanna et al.[24]	3	N = 36 Open label Chronic Schiz. WPRS, LFFMBS	TFD	1.5	25 (69%) subjects showed improvement (19 showed marked improvement, and 7 showed fair improvement) The improvement was significantly more for subjects without family history of schizophrenia On WPRS, mean scores decreased on depressive state, schizophrenic excitement and hebephrenic syndromes On LFFMBS, there was significant improvement in behavioral response to meal, attention to dress and personal cleanliness, speech and toilet behavior and response to psychiatrists, psychologists, nurses, etc	14 subjects developed EPS, which responded to either dose reduction or adding antiprakinsonian medications No significant side effects such as, drowsiness, orthostatic hypotension, GI disturbances, skin reaction etc, were noticed
Sharma and Dutta[25]	4	N = 34; Schiz, DBPCT (5 stage trt- withdrawal of previous trt to rando mization)	PMZ vs. PBO	1-5	Of the 19 patients treated with PMZ, 11(57.89%) showed moderate to marked improvement, no subject improved in PBO group and the difference between the 2 groups was significant.	Four patients had drowsiness and weakness, 1 patient became more aggressive with increased psychomotor activity, one patient developed severe tremors, rigidity and oculogyric crisis
Bagadia et al.[26]	2 phases of 3 month each	N = 50;DBCT cross over trial Schiz with optimal level of improve ment (>50% on BPRS were recruited), BPRS	PMZ vs. TFP	PMZ -2 TFP-10	Equal number of subjects dropped out of either drug There was no statistical difference in the number of subjects who showed further improvement, maintained same or worsened further No significant difference was noted between the two groups on improvement on BPRS at 3 months or improvement between 3 and 6 months	2 subjects with TFP had EPS (parkinsonian features and akathesia) 1 patient on PMZ had tremor and hypotension
Dube and Sethi[27]	6	N = 60 Schizophrenia DBCT cross over trial MBPRS, CGIS	Li vs CPZ		On modified BPRS, overall CPZ was better than Li for majority of the items for most of the time On CGIS both Li and CPZ showed significant improvement from the 2nd week onwards From week 1-4, CPZ was better than Li in improvement in severity of illness After 1st and 3rd week of treatment, CPZ was better than Li in global improvement	Not reported by authors
Sethi and Bhiman[28]	4	N = 30 Feighner’s criteria, Schiz, BPRS, Side effects symptoms checklist, CGIS, DBCT	TFP vs TFP-THF	TFP-5 TFP-THF (5/2)	The combination of THF does not reduce clinical efficacy of TFP.	The incidence of side effects is lower in the group receiving the combination (except dryness of mouth) whereas rigidity and muscle spasm are entirely absent.
Channabasavanna and Michael[29]	12 weeks (mainte nance phase)	N = 30; DSM-III Chronic Schiz DBCT, SAPS, SANS, SAS	Penflu ridol vs. PBO vs. HPL	60 mg/week	Penfluridol was significantly better than placebo for maintenance therapy In case of worsening of condition, the patient was given HPL Only 1 patient in the Penfluridol group required supplemental haloperidol while 12 among the placebo group did Penfluridol was as efficacious as HPL for maintenance therapy	EPS were noted No serious S/E were encountered General physical condition and blood chemistry, hematological investigations and urine analysis not revealed any abnormality

Schiz - Schizophrenia; DBPCT - Double blind placebo controlled trial; PCPZ - Prochloperazine; PBO - Placebo; EPS - Extrapyramidal symptoms; TRZ - Thioridazine; S/E - side effect; FFP - Fluphenazine; TPZ - Thioproperazine; CVs. - Cardiovascular system; RCT - Randomized controlled trial; MMPI - Minnesota multiphasic personality inventory; TAT - Thematic apperception test; TFP - Trifluoperazine; UCPZ - Unichlorpromazine; THF - Trihexyphenidyl; HPL- Haloperidol; CPZ- Chlorpromazine; PSSR - Psychotic symptom severity rating chart; DBRCT - Double blind randomized controlled trial; GI - Gastrointestinal; LFT-Liver function test; RFT - Renal function test; DBCT - Double blind controlled trial; FFX - Fluphenthixol; TFD - Trifluperidol; QPSS - Quantification of psychotic symptom severity; WBRS - Wing’s behavior rating scale; CNS - Central nervous system; PMZ - Pimozide; MSQ - Mental status questionnaire; SMSQ - Special mental status questionnaire; WPRS - Wittenborn psychiatric rating scale; LFFMBS - L-M fergus falls behavior schedule; BPRS - Brief psychiatric rating scale; Li- lithium; MBPRS - Modified brief psychiatric rating scale; CGI-S - Clinical global impression severity; SAPS - Scale for assessment of positive symptoms; SANS - Scale for assessment of negative symptoms; SAS - Simpson and angus rating scale for extrapyramidal side effects