Comparison of efficacy of haloperidol and olanzapine in the treatment of delirium.

OBJECTIVE: Till date, typical antipsychotic haloperidol is the treatment of choice for delirium. But, due to higher side effects with haloperidol, newer atypical antipsychotics (e.g., olanzapine) are increasingly being used in the treatment of delirious patients. The aim of the current research was to study the efficacy and tolerability of haloperidol and olanzapine in the treatment of delirium.
MATERIALS AND METHODS: This was an open-label, randomized controlled study carried out in a tertiary care hospital at Chandigarh, India. A total of 100 patients admitted in medicine, surgery, and orthopedic wards and diagnosed as having delirium on Confusion Assessment Method scale were included in the study. Patients were given either haloperidol (1-4 mg/day either orally or by nasogastric tube) or olanzapine (2.5-10 mg/day either orally or by nasogastric tube). Severity of delirium and pattern of symptom improvement were assessed by Memorial Delirium Assessment Scale (MDAS). Extrapyramidal side effects were assessed by Simpson-Angus Scale.
RESULTS: There was an improvement in delirium severity in both groups with treatment. Mean daily dose of haloperidol and olanzapine used per patient was 2.10 and 5.49 mg, respectively, and the mean duration of treatment in olanzapine group and haloperidol group was 3.57 days and 3.37 days, respectively. There was no significant difference in the mean duration of treatment in both groups. At the end of study period, the MDAS scores in olanzapine and haloperidol groups were 8.43 and 8.00, respectively, and the difference was not significant statistically with P = 0.765. Five patients experienced drug-related mild side effects.
CONCLUSION: Low-dose haloperidol and olanzapine were equally efficacious and well tolerated in delirium.

INTRODUCTION

Delirium is a complex neuropsychiatric condition common in hospitalized patients. It is characterized by altered level of consciousness, inattention, disorientation, disorganized thinking, altered sleep–wake cycle, altered psychomotor activity, and perceptual abnormality due to one or more structural and/or physiological abnormalities directly or indirectly affecting the brain. Delirium is typically abrupt in onset and fluctuating in nature.[1] Delirium is associated with 6%–18% risk of death, increased hospital stay, caregiver burden, and increased treatment cost.[23]

Antipsychotics are the mainstay of treatment for delirium except for delirium due to alcohol or benzodiazepine withdrawals.[4] Haloperidol is the gold standard of treatment.[5] Recent studies have compared the role of various typical (chlorpromazine)[6] and atypical antipsychotics (risperidone);[789] olanzapine[10111213141516] and quetiapine[1718] in delirium.

There have been three single-agent studies and seven comparison studies for the use of olanzapine in delirium.[101112131415161718192021] However, the available studies on the use of olanzapine in delirium had various shortcomings, for example, sample size was smaller,[1213141516] randomization was not done,[101213141521] lack of standard method of assessment, and infrequent follow-ups.[101416]

A recent meta-analysis of 15 studies found that second-generation antipsychotics may treat delirium better than placebo, usual care, or haloperidol.[22]

Furthermore, no study till date has studied the pattern of various symptom improvement in delirium.

Hence, we planned to conduct a randomized controlled study on 100 delirious patients to compare the efficacy of olanzapine and haloperidol in delirium. We also studied the phenomenology of delirium and pattern of various symptom improvement with treatment.

MATERIALS AND METHODS

Type of study

This was an open-label, randomized controlled study. Randomization was done using a computer-generated random number table.

Aims and objectives

Our primary aim was to compare the efficacy and tolerability of olanzapine and haloperidol in delirium. Our secondary aim was to study the phenomenology of delirium and pattern of symptom improvement with treatment.

Patients

The study was done on delirious patients admitted in medicine emergency ward and patients referred to consultation liaison services of the Department of Psychiatry, Government Medical College and Hospital, Chandigarh, India. Data collection was done from December 2011 to December 2012.

Patients who were above 18 years of age, verbally responsive, and not having dementia were included in the study. Patients who were mechanically ventilated, mute, currently taking antipsychotic drugs due to any reasons, having alcohol or benzodiazepine withdrawal delirium, or hypersensitivity to either haloperidol or olanzapine in the past were excluded from the study.

One hundred and thirty-two consecutive patients meeting the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria for the diagnosis of delirium after detection of delirium using Confusion Assessment Method (CAM) were recruited. Thirty-two patients dropped out of the study after randomization; due to death, transfer to ICU and transfer to other hospitals, or discharge against medical advice. These 32 dropped-out patients were excluded from the final analysis. One hundred patients completed the study and were included in the final analysis.

Assessment method

Each patient's sociodemographic and clinical variables were recorded on a pro forma designed for the study. CAM[23] was used to detect delirium and patients were diagnosed as per the DSM-IV criteria for delirium. Phenomenology and delirium severity were assessed by Memorial Delirium Assessment Scale (MDAS).[24] Drug-induced side effects were assessed using a pro forma specially designed for the study. Simpson–Angus Scale (SAS)[25] was used to assess extrapyramidal side effects.

Patients were rated systematically with the MDAS as a measure of delirium severity and phenomenology. Delirium severity was rated as “mild” delirium reflected by MDAS score ≤15, “moderate” severity delirium by MDAS scores of 16–22, and “severe” delirium as MDAS scores of 23–30. A score of ≤10 on MDAS was taken as the indicator of delirium resolution.[10]

Intervention

Patients were randomized into two groups. Intervention was done on the basis of a computer-generated random number table. One group received atypical antipsychotic olanzapine and the other group received typical antipsychotic haloperidol. Drugs were given by enteral route only either orally or by nasogastric tube. Doses of olanzapine and haloperidol were used on the basis of delirium severity as assessed by MDAS scores as shown in Table 1.

Table 1

Doses of olanzapine and haloperidol used and Memorial Delirium Assessment Scale scores

Response to the treatment was assessed by improvement on MDAS scores. Assessment was done every 24 h by the principal investigator till resolution of delirium. Follow-up assessment of each patient was done at the same time of day at which he/she was first assessed. Pattern of symptom improvement was noted and compared between both the groups. Total time taken for the resolution of delirium was noted and compared.

Statistical analysis

Chi-square test was used to compare the sociodemographic profile and variables related to clinical profile (nominal data) in both groups. Data analysis was performed using the SPSS (version 21) statistical software package for Windows (SPSS Inc., Chicago, IL, USA). The analyzed data were represented in percentage and mean. Level of significance was set at P < 0.05.

The study was registered with the Clinical Trial Registry-India CTRI/2016/10/007331.

The confidentiality of the information obtained was maintained and the principles enunciated in the Declaration of Helsinki were complied with. Indian Council of Medical Research's ethical guidelines for biomedical research on human subjects were adhered to.[26]

The study was approved by the local Institutional Ethics Committee.

RESULTS

One hundred and thirty-two patients were recruited for the study. Thirty-two patients dropped out; 19 from olanzapine group and 13 from haloperidol group. Out of the 32 dropped-out cases, 16 died, 9 were shifted to ICU and could not be assessed further, and 7 patients were either transferred to other hospital or got discharged against medical advice. Totally 100 patients were included in the final analysis; 47 in olanzapine group and 53 in haloperidol group as shown in Figure 1.

Figure 1

Flow Chart

There was no statistically significant difference in the sociodemographic profile, clinical variable, and biochemical parameters in olanzapine and haloperidol groups and both groups were comparable to each other.

Delirium severity

Mean MDAS score at baseline was 18.49 in olanzapine group and 17.79 in haloperidol group. Both groups were comparable in the severity of delirium at baseline and the difference was not significant (P = 0.791).

At the end of the study period, the MDAS scores in olanzapine and haloperidol groups were 8.43 and 8.00, respectively, and the difference was not significant statistically with P = 0.765.

Phenomenology of delirium

The various symptoms of delirium in both the groups were; disorientation, impaired digit span, reduced ability to shift attention, decreased or increased psychomotor activity, short term memory impairment, sleep-wake cycle disturbance, reduced level of consciousness, perceptual disturbance and delusions as shown in Table 2.

Table 2

Number of patients in which various symptoms of delirium were present and number of patients in which symptoms improved with treatment

Pattern of symptom improvement

Overall, there was improvement in all the symptoms of delirium with treatment and at the end point there was no significant difference between both groups in any of the symptoms.

During the study period, few symptoms improved earlier in one group than the other. Severity of inattention on day 2 and severity of disorganized thinking on days 2 and 3 were significantly lesser in olanzapine group than that of haloperidol group (P < 0.05). Severity of perceptual disturbances on day 4 and severity of psychomotor disturbances on days 3 and 4 were significantly less in haloperidol group than that of olanzapine group (P < 0.05).

Dose of antipsychotic used

Mean daily dose of olanzapine used was 5.49 mg (range = 2.5 mg) and mean daily dose of haloperidol was 2.10 mg (range = 1–5 mg). In terms of chlorpromazine equivalents, mean daily doses of antipsychotics used were 109.8 and 105, respectively, in olanzapine and haloperidol groups.

Duration of treatment

The mean duration of treatment in olanzapine group and haloperidol group was 3.57 days and 3.37 days, respectively, and the difference between two groups was not statistically significant with P = 0.233.

Drug-related adverse effects

Totally five patients had drug-related side effects; two in olanzapine group and three in haloperidol group. One patient in olanzapine group had excessive sedation and one had developed akathisia. All the three patients in haloperidol group had drug-induced parkinsonism. Four out of the five patients were >55 years old and were male.

Side effects were mild in severity and no change in drug dose and scheduling was required due to these side effects. No anti-parkinsonism drug or other drug was given to counter these side effects. No change in metabolic profile was observed during the study period.

DISCUSSION

In the present study, impaired attention, disorientation, and altered psychomotor activity were the most common symptoms present in delirious patients.

Mean daily doses of olanzapine and haloperidol required in the study population were 5.49 mg and 2.10 mg, respectively. Mean daily dose of antipsychotics (olanzapine and haloperidol) in terms of chlorpromazine equivalents was 109.8 mg and 105 mg, respectively. This is in accordance with the previous studies where lesser than usual antipsychotic doses are required to treat delirium. Our study results are in concordance with the earlier studies where mean daily doses in the range of 37.5–169 mg chlorpromazine equivalent are sufficient to treat delirium.[61013151727]

Mean duration of treatment was calculated as the mean time taken by each patient from the start of treatment to resolution of delirium. Mean duration of treatment in our study was 3.47 ± 0.82 days. Mean duration of treatment in olanzapine group was 3.57 ± 0.92 days. Mean duration of treatment in haloperidol group was 3.37 ± 0.71 days. The results between the two groups were not statistically significant from each other. Our results match with the previous studies where mean time to improvement was 3.8–4.8 days.[8132829]

In the current study, there was 54.7% reduction in mean MDAS scores (54.4% in olanzapine group and 55% in haloperidol group). The study results correlate with the previous studies where there was reduction of 7%–70% in various delirium rating scales over the study period.[610121316172830]

There was an improvement in all domains of delirium, i.e., consciousness, attention and concentration, memory, thinking, psychotic symptoms, psychomotor activity, and sleep with treatment in both groups. Moreover, there was no significant difference in the final scores in any domain between both groups.

However, the earlier improvement of few symptoms such as impaired attention and disorganized thinking in one group over the other can be explained in terms of pharmacodynamic properties of the drugs.

Both inability to maintain and shift attention and disorganized thinking are cognitive phenomenon. Atypical antipsychotics such as olanzapine substantially block cortical serotonergic receptors (5HT2A). Serotonin inhibits the release of dopamine. Hence, when serotonin is blocked, dopamine concentration is increased at mesocortical pathway which is associated with cognition and socialization. However, haloperidol, being a typical antipsychotic, nonselectively blocks dopamine at D2 receptors in mesolimbic, mesocortical, and nigrostriatal pathways. Hence, increase in dopamine at mesocortical pathway may be responsible for the early and better improvement in ability to maintain and shift attention and disorganized thinking in olanzapine group than haloperidol group.[3132]

Half-lives of haloperidol and olanzapine are 12–36 h and 21–54 h, respectively. Time taken to reach peak plasma concentration after oral dose is 1–4 h for haloperidol and 2–6 h for olanzapine. Any drug usually needs up to 5 half-life to reach a steady-state plasma concentration. Steady-state concentration is reached within 3–5 days in haloperidol due to short half-life and it takes even up to 7 days in case of olanzapine to reach steady-state concentration. Effect on psychotic symptoms (delusions and hallucinations) and psychomotor activity depends on effective blockade of dopamine in mesolimbic and nigrostriatal pathways. Haloperidol attains steady-state concentration earlier, so it acts faster and hence leads to earlier improvement in perceptual and psychomotor disturbances than that of olanzapine group. Overall, five patients had minor adverse effects related to antipsychotics (2 out of 47, i.e., 4.25% in olanzapine group and 3 out of 53, i.e., 5.6% in haloperidol group). Sedation can be explained in terms of more anticholinergic effects of olanzapine and Extra Pyramidal Symptoms (EPS) due to blockage of nigrostriatal pathway by haloperidol.

None of the side effects were of such severe intensity that required stopping the drugs or any change in the doses of the drugs. This can be understood in terms of low doses of antipsychotics used as well as the short duration of treatment required in the treatment of delirium. Our results correlate with that of the earlier studies where side effect prevalence between 0% and 40% has been reported depending on the drugs used, its dosages, and duration of treatment of delirium.[61315283033]

Strengths and limitations of study

It was a randomized controlled study. Randomization was done using a computer-generated random number table. A total of 100 patients were included in the final analysis. Hence, the number of cases studied was higher than most of the earlier studies. Active case finding was done in medicine emergency using CAM. This prevented any bias in the study sample. Valid scales with high specificity and sensitivity, i.e., CAM, MDAS, and SAS were used in the study. Patients were followed up every 24 h till resolution of delirium.

However, certain limitations need to be considered while interpreting the results. It was a single-blind study and interviewer was not blind to the treatment given. Hence, it could lead to interviewer bias in the study population. Placebo arm was not included. Patients who were more severely ill, unable to speak, mechanically ventilated, and who could not consume oral medicines were excluded from the study. This possibly resulted in the inclusion of more mild-to-moderate cases in our study. This possibly resulted in bias in our results, i.e., higher response rate and less mean duration of treatment in our study.

CONCLUSION

Overall, patients with delirium responded well to low doses of both haloperidol and olanzapine. Patients tolerated both drugs equally well that can be expected due to low mean daily doses of drugs as well as shorter duration of treatment required in delirium.

At the end of the study period, there was no significant difference in response to both drugs in all the domains, i.e., consciousness, memory, attention and concentration, thinking, perception of psychomotor activity, and sleep–wake cycle.

Hence, we can conclude that both olanzapine and haloperidol can be safely used in the treatment of delirious patients, and low doses of antipsychotics for short duration are usually sufficient.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.