Chlorpromazine Vs. Other Antipsychotics

Chlorpromazine vs. Other Antipsychotics Replacement/Addition to the List

Peer Feedback: Multiple feedback obtained about replacement of chlorpromazine, also addition of quetiapine.

“replace with clozapine – Clozapine, although it has many adverse effects, is the most effective for treating schizophrenia.”

“Chlorpromazine tends to be one of the worst tolerate antipsychotics Quetiapine is an effective antipsychotic and has reasonable evidence as adjunct therapy in depression and bipolar disorder” “Current use (of quetiapine) exceeds evidence, but not including this would involve major shifts in prescribing and may be difficult” “Better options already on the list, e.g. Haldol”

“Clozapine. Unique. Only medication for treatment resistant schizophrenia. Not sure CPZ is essential since have other 1st and 2nd generation antipsychotic options (haloperidol, risperidone). Could consider a first generation depot formuation option.”

Note: Chlorpromazine and Haloperidol are 1st generation anti-psychotics; quetiapine, risperidone and clozapine are 2nd generation antipsychotics. Chlorpromazine, Haloperidol, and Risperidone are on the list.

Literature Review Questions:

What is the most efficacious treatment for schizophrenia? Is Quetiapine more efficacious than Chlorpromazine? Is Clozapine more efficacious than Chlorpromazine? Is Haldol more efficacious than Chlorpromazine? What is Quetiapine’s role in treating bipolar disorder and depression?

Literature Search: Cochrane Review “antipsychotics AND efficacy AND (Chlorpromazine OR Haloperidol OR Quetiapine OR Clozapine)” Pubmed “chlorpromazine AND ((haloperidol OR haldol) OR quetiapine OR clozapine) AND efficacy AND meta-analysis/review”, CPG via the CMA ‘psychoses’ eCPS - Psychiatric Disorders: Psychoses

Haloperidol versus first-generation antipsychotics (Cochrane 2015)

The systematic review currently includes 63 randomised trials with 3675 participants. Bromperidol (n = 9), loxapine (n = 7), and trifluoperazine (n = 6) were the most frequently administered antipsychotics comparator to haloperidol. The included studies were published between 1962 and 1993, were characterised by small sample sizes (mean: 58 participants, range from 18 to 206) and the predefined outcomes were often incompletely reported. All results for the main outcomes were based on very low or low quality data. In many trials the mechanism of randomisation, allocation, and blinding was frequently not reported. In short-term studies (up to 12 weeks), there was no clear evidence of a difference between haloperidol and the pooled group of the other first- generation antipsychotic agents in terms of the primary outcome “clinically important response to treatment” (40 RCTs, n = 2132, RR 0.93 CI 0.87 to 1.00). In the medium-term trials, haloperidol may be less effective than the other first-generation antipsychotic group but this evidence is based on only one trial (1 RCT, n = 80, RR 0.51 CI 0.37 to 0.69). Based on limited evidence, haloperidol alleviated more positive symptoms of schizophrenia than the other antipsychotic drugs. There were no statistically significant between-group differences in global state, other mental state outcomes, behaviour, leaving the study early due to any reason, due to inefficacy, as well as due to adverse effects. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term.

The findings of the meta-analytic calculations support the statements of previous narrative, unsystematic reviews suggesting comparable efficacy of first-generation antipsychotics. In efficacy-related outcomes, there was no clear evidence of a difference between the prototypal drug haloperidol and other, mainly high-potency first-generation antipsychotics. Additionally, we demonstrated that haloperidol is characterised by a similar risk profile compared to the other first- generation antipsychotic compounds. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term. The results were limited by the low methodological quality in many of the included original studies. Data for the main results were low or very low quality. Therefore, future clinical trials with high methodological quality are required.

Dold, Markus, et al. "Haloperidol versus first-generation antipsychotics for the treatment of schizophrenia and other psychotic disorders." status and date: New, published in 1 (2015).

Chlorpromazine versus every other antipsychotic for schizophrenia (2014)

Samara, Myrto T., et al. "Chlorpromazine versus every other antipsychotic for schizophrenia: A systematic review and meta-analysis challenging the dogma of equal efficacy of antipsychotic drugs." European Neuropsychopharmacology 24.7 (2014): 1046-1055.

2014 Delirium Guideline (Canadian Coalition for Seniors’ Mental Health) Canadian Coalition for Seniors’ Mental Health; 2014 Guideline Update: The Assessment and Treatment of Delirium

15 antipsychotic drugs in schizophrenia - meta-analysis (2013)

We emphasise that the differences in efficacy between drugs were small (standardised mean differences 0·11–0·55, median 0·24), and smaller overall than those for side-effects. However, for perspective, the efficacy differences compared with placebo were of only medium size (0·33– 0·88, median 0·44), so the differences in efficacy between drugs are possibly substantial enough to be clinically important. Finally, because most clozapine studies were done in refractory patients, clozapine is thought to be superior only in this subtype, but in our analysis of non- refractory patients it was also more effective than all the other drugs. However, this result has the limitation that it was mainly based on older comparisons of clozapine with first-generation drugs.

All-cause discontinuation has previously been used as a measure for the acceptability of treatments, because it encompasses efficacy and tolerability.7,8 In our analysis, the results paralleled the efficacy findings in that the most effective drugs also had the lowest discontinuation rates (although haloperidol, the worst drug with respect to all-cause discontinuation, had a middle rank for efficacy).

Haloperidol caused the most extrapyramidal side effects, followed by zotepine and chlorpromazine. Chlorpromazine did not produce significantly more extrapyramidal side-effects than did most second generation antipsychotics. Haloperidol doses lower than 7·5 mg per day (the lowest dose in multiple-episode patients was 4 mg per day) produced similar outcomes for efficacy and extrapyramidal side-effects as did higher doses. Clozapine has a low intrinsic risk of extra pyramidal side-effects and might suppress both of these effects.

Weight gain and associated metabolic problems are regarded as the major issues associated with new antipsychotic drugs. Indeed, olanzapine, zotepine, and clozapine were the worst in this respect, and some guidelines recommend against the first-line use of olanzapine for first-episode patients.12 However, ziprasidone and lurasidone (along with haloperidol) were the only antipsychotic drugs without significantly more weight gain than placebo in adults. By contrast, chlorpromazine was among the worst drugs in this respect. Overall, our results with respect to sedation were reasonable, and direct and indirect comparisons were consistent. For example, clozapine and chlorpromazine are certainly sedating drugs; the good results for amisulpride can be accounted for by the absence of blockade of histaminergic receptors associated with sedation; and the small sedative effects of paliperidone can possibly be accounted for by its slow release mechanism limiting plasma peaks after ingestion.

QTc prolongation can lead to life-threatening torsades de pointes.50 The antipsychotic drugs assessed differed enormously with respect to this outcome, with some not differing from placebo, and one (sertindole) being almost one standard deviation worse. Indeed, sertindole was associated with increased cardiac mortality compared with risperidone in a large, pragmatic, randomised controlled trial51 (n=9858, all-cause mortality not different). In another study, 52 no difference in frequency of sudden death was seen between ziprasidone (the third worst drug in our analysis) and olanzapine (n=18 154).51 We emphasise that amisulpride was regarded as benign in some guidelines,13 but our findings show that it might not be—a result that is consistent with an analysis of amisulpride overdoses.50

Paliperidone and risperidone increased prolactin by more than one standard deviation compared with placebo; aripiprazole reduced prolactin (although not significantly) because of its partial- dopamine-agonist properties. Despite the collaboration of its manufacturer, no useable data on amisulpride were available, but its high prolactin risk is well known.54 Leucht, Stefan, et al. "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis." The Lancet382.9896 (2013): 951-962. Cochrane Quetiapine vs Atypical Antipsychotics (2013)

Efficacy data tended to favour the control drugs over quetiapine (Positive and Negative Syndrome Scale (PANSS) total score vs olanzapine: 11 RCTs, n = 1486, mean quetiapine endpoint score 3.67 higher, CI 1.95 to 5.39, low quality; vs risperidone: 13 RCTs, n = 2155, mean quetiapine endpoint score 1.74 higher,CI 0.19 to 3.29, moderate quality; vs paliperidone: 1 RCT, n = 319, mean quetiapine endpoint score 6.30 higher, CI 2.77 to 9.83, moderate quality), but the clinical meaning of these data is unclear. No clear mental state differences were noted when quetiapine was compared with clozapine, aripiprazole or ziprasidone. Compared with olanzapine, quetiapine produced slightly fewer movement disorders (7 RCTs, n = 1127, RR use of antiparkinson medication 0.51, CI 0.32 to 0.81, moderate quality) and less weight gain (8 RCTs, n = 1667, RR 0.68, CI 0.51 to 0.92, moderate quality) and glucose elevation, but increased QTc prolongation (3 RCTs, n = 643, MD 4.81, CI 0.34 to 9.28). Compared with risperidone, quetiapine induced slightly fewer movement disorders (8 RCTs, n = 2163, RR use of antiparkinson medication 0.5, CI 0.36 to 0.69, moderate quality), less prolactin increase (7 RCTs, n = 1733, MD -35.25, CI -43.59 to -26.91) and some related adverse effects but greater cholesterol increase (6 RCTs, n = 1473,MD8.57, CI 4.85 to 12.29). On the basis of limited data, compared with paliperidone, quetiapine induced fewer parkinsonian side effects (1 RCT, n = 319, RR use of antiparkinson medication 0.64, CI 0.45 to 0.91, moderate quality) and less prolactin increase (1 RCT, n = 319, MD -49.30, CI -57.80 to -40.80) and weight gain (1 RCT, n = 319, RR weight gain of 7% or more of total body weight 2.52, CI 0.5 to 12.78, moderate quality). Compared with ziprasidone, quetiapine induced slightly fewer extrapyramidal adverse effects (1 RCT, n = 522, RR use of antiparkinson medication 0.43, CI 0.2 to 0.93, moderate quality) and less prolactin increase. On the other hand, quetiapine was more sedating and led to greater weight gain (2 RCTs, n = 754, RR 2.22, CI 1.35 to 3.63, moderate quality) and cholesterol increase when compared with ziprasidone.

Available evidence from trials suggests that most people who start quetiapine stop taking it within a few weeks (around 60%). Comparisons with amisulpride, sertindole and zotepine do not exist. Although efficacy data favour olanzapine and risperidone compared with quetiapine, the clinical meaning of these data remains unclear. Quetiapine may produce fewer parkinsonian effects than paliperidone, aripiprazole, ziprasidone, risperidone and olanzapine. Quetiapine appears to have a similar weight gain profile to risperidone, as well as clozapine and aripiprazole (although data are very limited for the latter two comparators). Quetiapine may produce greater weight gain than ziprasidone and less weight gain than olanzapine and paliperidone.Most data that have been reported within existing comparisons are of very limited value because of assumptions and biases within them.Much scope is available for further research into the effects of this widely used drug.

Clinicians should know that for only six of nine possible comparisons of quetiapine with other second-generation antipsychotic drugs, relevant studies were identified, and that the evidence is limited because very high numbers of participants leave the studies early. Our most robust finding is that most people who are started on quetiapine will be off this drug within a few weeks.

Asmal, Laila, et al. "Quetiapine versus other atypical antipsychotics for schizophrenia." The Cochrane Library (2013).

Cochrane Haldol vs Chlorpromazine (2008) We found 14 relevant studies, mostly of short duration, poorly reported and conducted in the 1970s (total n=794 participants). Nine of these compared oral formulations of both compounds, and five compared intramuscular formulations. Haloperidol was associated with significantly fewer people leaving the studies early (13 RCTs, n=476, RR 0.26 CI 0.08 to 0.82). The efficacy outcome ’no significant improvement’ tended to favour haloperidol, but this difference was not statistically significant (9 RCTs, n=400, RR 0.81 CI 0.64 to 1.04). Movement disorders were more frequent in the haloperidol groups (’at least one extrapyramidal side effect’: 6 RCTs, n=37, RR 2.2 CI 1.1 to 4.4, NNH5 CI 3 to 33), while chlorpromazine was associated with more frequent hypotension (5 RCTs, n=175, RR 0.31 CI 0.11 to 0.88, NNH 7 CI 4 to 25). Similar trends were found when studies comparing intramuscular formulations and studies comparing oral formulations were analysed separately.

Given that haloperidol and chlorpromazine are global standard antipsychotic treatments for schizophrenia, it is surprising that less than 800 people have been randomised to a comparison and that incomplete reporting still makes it difficult for anyone to draw clear conclusions on the comparative effects of these drugs. However, it seems that haloperidol causes more movement disorders than chlorpromazine, while chlorpromazine is significantly more likely to lead to hypotonia. We are surprised to have to say that we feel further, large, well designed, conducted and reported studies are required.

Although haloperidol and chlorpromazine have been the standard drugs in the treatment of schizophrenia for many years, there are relatively few studies investigating their efficacy and tolerability head to head. There were no statistically significant efficacy differences between the two compounds, but the side-effect profiles differ. Extrapyramidal side effects seem to be more frequent when haloperidol is used, in comparison to which more hypotension is associated with chlorpromazine treatment. Haloperidol and chlorpromazine are relatively cheap drugs, at least compared to new, so called ’atypical’ antipsychotics. From the results of this review no definite conclusions on the relative efficacy of the two compounds can be drawn, but their side-effect profiles differ.

Leucht, Claudia, et al. "Haloperidol versus chlorpromazine for schizophrenia."Cochrane Database Syst Rev 1 (2008).

eCPS (2014) Class Drug Dose Adverse Effects Drug Interactions Comments Costa Antipsychotics, chlorpromazine Initial:50–100 More common with low- Additive effects with other Advise patients $$ First- generics mg/day po potency agents: sedation, CNS depressants, about generation, low Usual:200–400 cardiovascular effects, anticholinergics, alpha- antipsychotic- potency mg/day po anticholinergic effects, adrenergic antagonists; associated weight gain, lower seizure inhibitors of cytochrome body Maximum:1000– threshold, P450 enzymes (e.g., TCAs, temperature 2000 mg/daypo photosensitivity. fluoxetine, fluvoxamine, dysregulation More common with high- paroxetine) may increase and prevention Divided in 1–3 potency agents: increased serum levels; inducers of of heat stroke doses/day prolactin, EPS, NMS, cytochrome P450 enzymes (e.g., tardive movement (e.g., carbamazepine, hydration, sun disorders. phenytoin) may decrease protection). serum levels; effects of Liver function levodopa may be inhibited. abnormalities. Antipsychotics, haloperidol Initial: 1.5–3 More common with low- Additive effects with other Advise patients $ First- generics mg/day po potency agents: sedation, CNS depressants, about generation, Usual: 4–12 cardiovascular effects, anticholinergics, alpha- antipsychotic- high potency mg/day po anticholinergic effects, adrenergic antagonists; associated weight gain, lower seizure inhibitors of cytochrome body Maximum: 20 threshold, P450 enzymes (e.g., TCAs, temperature mg/day po photosensitivity. fluoxetine, fluvoxamine, dysregulation More common with high- paroxetine) may increase and prevention Divided in 1–3 potency agents: increased serum levels; inducers of of heat stroke Class Drug Dose Adverse Effects Drug Interactions Comments Costa doses/day prolactin, EPS, NMS, cytochrome P450 enzymes (e.g., tardive movement (e.g., carbamazepine, hydration, sun disorders. phenytoin) may decrease protection). serum levels; effects of Liver function levodopa may be inhibited. abnormalities. Legend: $ < $25 $$ $25–50 $$$ $50–75 $$$$ $75–100

Class Drug Dose Adverse Effects Drug Interactions Comments Costa Antipsychotics, clozapine Initial:12.5–25 Agranulocytosis Additive sedation with CNS Advise $$ Second- Clozaril, generics mg/day po (<1%), seizures (1– depressants; may potentiate patients about generation Titration: 5%; dose-related), antihypertensive drug effects; antipsychotic- Increase by 12.5– sedation, orthostatic inhibitors of CYP1A2, such as associated 25 mg on 2nd day hypotension, diltiazem, fluvoxamine or body and then by 25– tachycardia, fever, propranolol, or of CYP3A4, such temperature 50 mg daily po nausea, weight gain, as clarithromycin, dysregulation depending on hypersalivation (30– erythromycin, grapefruit juice and tolerance 50%), urinary or prednisone, may increase prevention of incontinence; clozapine levels; inducers of heat stroke Usual:300–600 increased risk of CYP1A2 or CYP3A4 such as (e.g., mg/day po diabetes and carbamazepine, phenytoin, hydration, hyperlipidemia; rifampin or cigarette smoking sun Maximum: 900 myocarditis and may reduce clozapine levels; protection). mg/day other cardiac effects respiratory depression with (seePharmacologic higher doses of Divided in 1–3 Choices). benzodiazepines; avoid use doses/day with bone marrow suppressants and drugs that lower the seizure threshold. Antipsychotics, quetiapine Initial: 50–100 Sedation, dizziness, Additive sedation with CNS Advise $ Second- immediate-release mg/day po weight gain, depressants; may potentiate patients about generation Seroquel, generics Titration: orthostatic antihypertensive drug effects; antipsychotic- Increase by 100 hypotension, hepatic inhibitors of CYP3A4 (e.g., associated mg/day aminotransferase clarithromycin, erythromycin, body elevation, headache, grapefruit juice, ketoconazole, temperature Usual: 600 anticholinergic prednisone) may increase dysregulation mg/day effects, increased quetiapine levels; inducers of and risk of diabetes and CYP3A4 (e.g., carbamazepine, prevention of Maximum:800 dyslipidemia, phenytoin, rifampin) may heat stroke mg/day(product possible increased decrease quetiapine levels. (e.g., monograph). risk of cataracts; hydration, Doses of up to may reduce thyroid sun 1200 mg/day hormone levels. protection). used in clinical practice under care of a psychiatrist

Divided in 1–3 doses/day Antipsychotics, quetiapine Initial: 300 mg Sedation, dizziness, Additive sedation with CNS Advise $ Second- extended-release QHS po (200 mg weight gain, depressants; may potentiate patients about generation Seroquel XR, for first-episode orthostatic antihypertensive drug effects; antipsychotic- generics psychosis) hypotension, hepatic inhibitors of CYP3A4 (e.g., associated Titration: May aminotransferase clarithromycin, erythromycin, body increase dose in elevation, headache, grapefruit juice, ketoconazole, temperature increments anticholinergic prednisone) may increase dysregulation of≤300 mg/day ateffects, increased quetiapine levels; inducers of and intervals ≥1 day risk of diabetes and CYP3A4 (e.g., carbamazepine, prevention of dyslipidemia, phenytoin, rifampin) may heat stroke Usual: 400–800 possible increased decrease quetiapine levels. (e.g., Class Drug Dose Adverse Effects Drug Interactions Comments Costa mg/day risk of cataracts; hydration, may reduce thyroid sun Given as a once- hormone levels. protection). daily dose, generally in the evening Antipsychotics, risperidone Initial:0.5–1 mg/day Sedation, headaches, Additive sedation with CNS  Advise$ Second- po weight gain, orthostatic depressants; may potentiate patients about generation Risperdal Titration: Increase hypotension, rhinitis, antihypertensive drug effects; antipsychotic- by 0.5–1 mg Preparations, generics anxiety, dose-related inhibitors of CYP3A4 (e.g., associated body poevery 3–4 days hyperprolactinemia and clarithromycin, erythromycin, temperature Usual:2–6 mg/day dysregulation EPS. grapefruit juice, ketoconazole, po and prevention Maximum: 6 mg/day prednisone) may increase of heat stroke po Risk of intraoperative risperidone levels; inducers of (e.g., hydration, Frequency: 1 floppy iris syndrome in CYP3A4 (e.g., carbamazepine, sun protection). dose/day, preferably patients undergoing phenytoin, rifampin) may decrease QHS cataract surgery who have been exposed to risperidone levels. risperidone. Antipsychotics, risperidone long- Initial: 25 mg im Sedation, headaches, Additive sedation with CNS  Advise$$$ Second- acting injection every 2 wk (oral weight gain, orthostatic depressants; may potentiate patients about generation supplementation hypotension, rhinitis, antihypertensive drug effects; antipsychotic- with current Risperdal Consta anxiety, dose-related inhibitors of CYP3A4 (e.g., associated body antipsychotic hyperprolactinemia and clarithromycin, erythromycin, temperature required for first 3 dysregulation EPS. grapefruit juice, ketoconazole, wk) and prevention Titration: Depending prednisone) may increase of heat stroke on response, Risk of intraoperative risperidone levels; inducers of (e.g., hydration, increase by 12.5 floppy iris syndrome in CYP3A4 (e.g., carbamazepine, sun protection). mg every 4–8 wk patients undergoing phenytoin, rifampin) may decrease Usual: 25–37.5 cataract surgery who risperidone levels. mgim every 2 wk. have been exposed to Some patients can risperidone. be maintained on a dose of 12.5 mg Adverse effects may be every 2 wk less severe compared to Maximum: 50 mg im oral risperidone due to every 2 wk decreased peak to trough serum fluctuations. Legend: $ < $150 $$ $150–350 $$$ $350–550

Extra- pyramidal Side Weight Metabolic Cardiovascular Drug Sedation Insomnia Effectsa Gain Abnormalitiesb Hyperprolactinemia Effectsc clozapine ++++ – – ++++ ++++ – ++ quetiapine +++ – – +++ ++ – + risperidone + + +++ ++ +/– +++ + Legend: ++++ = high; +++ = moderate; ++ = low; + = very low; +/– = minimal or none; – = equivalent to placebo

Psychiatric Disorders: Psychoses; Heather Milliken, MDCM, FRCPC, CSPQ; Date of revision: September 2014 Quetiapine CPS for depression and bipolar disorder (2015)

Extended-release quetiapine, a second-generation or “atypical” antipsychotic agent, has been approved in Canada for the treatment of depression and is considered to be a second-line option.20 , 42

Psychiatric Disorders: Depression; Sidney H. Kennedy, MD, FRCPC, Sagar V. Parikh, MD, FRCPC, and Sophie Grigoriadis, MD, PhD, FRCPC; Date of revision: March 2015

Quetiapine is listed as a first line therapy in Pharmacologic Management of Acute Mania, Acute Depression, and Maintenance Treatment Regimens for Bipolar Disorder.

Psychiatric Disorders: Bipolar Disorder; Sagar V. Parikh, MD, FRCPC; Date of revision: April 2015

Contraindications (CI), Adverse Effects Initial dose; typical Medication Uses drug interactions (DI) or (common and Monitoring dose cautions severe) Chlorpromazine delusions, CI: comatose states or the drowsiness, jaundice, 10mg; 10mg every 8-6 dementia, presence of large amounts of agranulocytosis, hours OR 25mg every 8-6 hallucinations, CNS depressants (alcohol, hypotensive effects, hours trirate 1-2days, by delirium in HIV, barbiturates, narcotics) ECG changes, EPS, 25-50mg semi-weekly, porphyria, DI: phenytoin, propanalol, tardive dyskinesia max 2000mg/day) schizophrenia thiazide diuretics, Porphyria: 25-50mg anticoagulants Increased every 8-6 hours risk for cardiovascular events in elderly haloperidol delusions, CI: severe toxic CNS delirium, confusion, 0.25mg; 0.25-0.5mg BP, clinical hallucinations, depression or comatose anticholinergic, every 8-12 hours worsening dementia states, parkinson’s, dementia- sedation, EPS, and suicidal related psychosis akathisia, risk, neuropleptic electrolytes malignant syndrome, tardive dyskinesia risperidone bipolar disorders, CI: epilepsy, thyrotoxicosis, increased appetite, 3mg; 3mg every 12 hours clinical irritability Parkinson’s disease, caution fatigue, nausea, worsening associated with with renal or hepatic vomiting, and suicidal autistic disorder, impairment, cardiovascular constipation, risk, signs of schizophrenia - disease, pregnancy parkinsonism, upper hypotension adults, DI: fluoxetine, paroxetine, abdominal pain, (BP) adolescents quinidine, carbamazepine, anxiety, dizziness, phenytoin, rifampin, tremor, sedation, phenobarbital Elderly akathisia, dystonia, patients at increased risk of blurred vision, death stomach discomfort