Key messages
We are very uncertain whether there is a difference between the two medications in terms of benefits.
Olanzapine may have slight advantages in terms of improving general state of mind (behaviour, mood, thoughts, perceptions, etc.) and may have some advantages in terms of quality of life.
People are more likely to gain weight with olanzapine and more likely to develop movement problems with haloperidol. People on haloperidol are more likely to stop taking their medication.
When choosing between haloperidol and olanzapine, factors to take into account are the person's preferences, characteristics such as their tendency to gain or lose weight and their experience with medications.
What is schizophrenia?
People with schizophrenia often hear voices, see things and have beliefs that others don't share. They may also feel very tired, have a lack of interest and may have trouble feeling emotions. This review is important because schizophrenia is a severe mental health condition, with an approximately 1% chance of being diagnosed over a person's lifetime.
What are haloperidol and olanzapine?
Haloperidol (pronounced HAL-oh-PER-i-dol) has been used in the treatment of schizophrenia for decades. It remains one of the most commonly prescribed treatments and has well-defined benefits. It also has some side effects such as restlessness, uncontrollable shaking, tremors and stiffness, especially at high doses. Olanzapine (pronounced oh-LAN-za-peen) is a newer medication. It has also been found to be useful in the treatment of schizophrenia, although it has its own side effects, weight gain being the most common. We wanted to better understand the differences in the clinical benefits of these medications and also to see which may be more suitable for use in lower-income countries as well as during humanitarian emergencies.
What did we want to find out?
Is haloperidol better than olanzapine in treating schizophrenia or schizophrenia-spectrum disorders?
What did we do?
We searched for randomised clinical trials that were carried out up to 14 January 2023. We looked for studies that randomly assigned people with schizophrenia and schizophrenia-spectrum disorders to receive haloperidol or olanzapine in tablet form. The review includes 68 studies with 9132 participants.
What did we find?
According to our findings, we are very uncertain whether there is a difference between the two medications in general clinically important change and relapse. However, olanzapine may result in a slightly greater improvement in mental state (general state of mind such as behaviour, mood, thoughts, perceptions, etc.) and may result in some improvement in quality of life. On other measures, haloperidol and olanzapine were similar in terms of benefits. Additionally, both medications showed side effects: participants taking haloperidol were more likely than those on olanzapine to experience problems with movement, and those on olanzapine were more likely to gain weight. However, it should be noted that there was considerable discrepancy between some of the studies. In addition, an increased number of people on haloperidol left the studies early due to side effects. While there is insufficient information to understand the reason for this finding, we hypothesise that this may be linked to the use of higher equivalent doses of haloperidol compared to olanzapine in some studies.
What are the limitations of the evidence?
Studies need to focus on and include outcomes that are relevant for people with schizophrenia and their families. Most studies focused on benefits within the first year of use, and have not taken into account other factors that could be of interest to people with lived experience of schizophrenia, such as ability to work, family impact, social function and acceptability to the user. While some studies measured relapse as an outcome, the definition of relapse did not always make clear whether it resulted in a person's hospitalisation. This is important for people with schizophrenia and their families because relapse and hospitalisation are dramatic and significant setbacks.
It is important to understand that many studies did not use equivalent doses of the two medications when they were compared. Most studies used comparatively higher doses of haloperidol compared to olanzapine, which could be associated with more side effects and related clinical outcomes for people on haloperidol in these studies.
It is important to keep in mind that on careful review we have low or very low confidence in the priority findings because the studies had some weaknesses.
How up-to-date is the evidence?
The evidence is up-to-date as of 14 January 2023.
Overall, the certainty of the evidence was low to very low for the main outcomes in this review, making it difficult to draw reliable conclusions. We are very uncertain whether there is a difference between haloperidol and olanzapine in terms of clinically important global state and relapse. Olanzapine may result in a slightly greater overall clinically important change in mental state and in a clinically important change in quality of life. Different side effect profiles were noted: haloperidol may result in a large increase in extrapyramidal side effects and olanzapine in a large increase in weight gain. The drug of choice needs to take into account side effect profiles and the preferences of the individual. These findings and the recent inclusion of olanzapine alongside haloperidol in the WHO Model List of Essential Medicines should increase the likelihood of it becoming more easily available in low- and middle- income countries, thereby improving choice and providing a greater ability to respond to side effects for people with lived experience of schizophrenia.
There is a need for additional research using appropriate and equivalent dosages of these drugs. Some of this research needs to be done in low- and middle-income settings and should actively seek to account for factors relevant to these. Research on antipsychotics needs to be person-centred and prioritise factors that are of interest to people with lived experience of schizophrenia.
Schizophrenia is often a severe and disabling psychiatric disorder. Antipsychotics remain the mainstay of psychotropic treatment for people with psychosis. In limited resource and humanitarian contexts, it is key to have several options for beneficial, low-cost antipsychotics, which require minimal monitoring. We wanted to compare oral haloperidol, as one of the most available antipsychotics in these settings, with a second-generation antipsychotic, olanzapine.
To assess the clinical benefits and harms of haloperidol compared to olanzapine for people with schizophrenia and schizophrenia-spectrum disorders.
We searched the Cochrane Schizophrenia study-based register of trials, which is based on monthly searches of CENTRAL, CINAHL, ClinicalTrials.gov, Embase, ISRCTN, MEDLINE, PsycINFO, PubMed and WHO ICTRP. We screened the references of all included studies. We contacted relevant authors of trials for additional information where clarification was required or where data were incomplete. The register was last searched on 14 January 2023.
Randomised clinical trials comparing haloperidol with olanzapine for people with schizophrenia and schizophrenia-spectrum disorders. Our main outcomes of interest were clinically important change in global state, relapse, clinically important change in mental state, extrapyramidal side effects, weight increase, clinically important change in quality of life and leaving the study early due to adverse effects.
We independently evaluated and extracted data. For dichotomous outcomes, we calculated risk ratios (RR) and their 95% confidence intervals (CI) and the number needed to treat for an additional beneficial or harmful outcome (NNTB or NNTH) with 95% CI. For continuous data, we estimated mean differences (MD) or standardised mean differences (SMD) with 95% CIs. For all included studies, we assessed risk of bias (RoB 1) and we used the GRADE approach to create a summary of findings table.
We included 68 studies randomising 9132 participants.
We are very uncertain whether there is a difference between haloperidol and olanzapine in clinically important change in global state (RR 0.84, 95% CI 0.69 to 1.02; 6 studies, 3078 participants; very low-certainty evidence).
We are very uncertain whether there is a difference between haloperidol and olanzapine in relapse (RR 1.42, 95% CI 1.00 to 2.02; 7 studies, 1499 participants; very low-certainty evidence).
Haloperidol may reduce the incidence of clinically important change in overall mental state compared to olanzapine (RR 0.70, 95% CI 0.60 to 0.81; 13 studies, 1210 participants; low-certainty evidence). For every eight people treated with haloperidol instead of olanzapine, one fewer person would experience this improvement.
The evidence suggests that haloperidol may result in a large increase in extrapyramidal side effects compared to olanzapine (RR 3.38, 95% CI 2.28 to 5.02; 14 studies, 3290 participants; low-certainty evidence). For every three people treated with haloperidol instead of olanzapine, one additional person would experience extrapyramidal side effects. For weight gain, the evidence suggests that there may be a large reduction in the risk with haloperidol compared to olanzapine (RR 0.47, 95% CI 0.35 to 0.61; 18 studies, 4302 participants; low-certainty evidence). For every 10 people treated with haloperidol instead of olanzapine, one fewer person would experience weight increase.
A single study suggests that haloperidol may reduce the incidence of clinically important change in quality of life compared to olanzapine (RR 0.72, 95% CI 0.57 to 0.91; 828 participants; low-certainty evidence). For every nine people treated with haloperidol instead of olanzapine, one fewer person would experience clinically important improvement in quality of life.
Haloperidol may result in an increase in the incidence of leaving the study early due to adverse effects compared to olanzapine (RR 1.99, 95% CI 1.60 to 2.47; 21 studies, 5047 participants; low-certainty evidence). For every 22 people treated with haloperidol instead of olanzapine, one fewer person would experience this outcome.
Thirty otherwise relevant studies and several endpoints from 14 included studies could not be evaluated due to inconsistencies and poor transparency of several parameters. Furthermore, even within studies that were included, it was often not possible to use data for the same reasons. Risk of bias differed substantially for different outcomes and the certainty of the evidence ranged from very low to low. The most common risks of bias leading to downgrading of the evidence were blinding (performance bias) and selective reporting (reporting bias).