Clozapine dose in schizophrenia

Background: Schizophrenia is a severe mental illness that affects thinking and perception. People with schizophrenia often experience profound disruptions in their speech, emotional processes, behaviour and sense of self. Antipsychotic medication can be a helpful treatment for schizophrenia; however, taking antipsychotic medication can have unpleasant effects. Clozapine is an antipsychotic drug that can be useful in treating schizophrenia, particularly when other antipsychotic medications have not worked. It is unclear, however, what dose of clozapine is most effective with the least side effects. This review investigates the effects of receiving clozapine at four different dose levels (high dose, standard dose, low dose, very low dose).

Searching: An electronic search for studies that randomised people with schizophrenia to receive different doses of clozapine was run in August 2011 and again on 8 December 2016.

Results: We found five studies with 452 participants which met our inclusion criteria. Each compared the effects of clozapine at very low dose (up to 149 mg/day), low dose (150 mg/day to 300 mg/day) and standard dose (301 mg/day to 600 mg/day). None of the studies examined the effects of clozapine at higher than the standard dose. There was nothing to choose between standard, low and very low doses in terms of body mass index (BMI) measurements in the short term. However, weight gain was greater in those receiving the standard dose compared to those receiving the low dose. The incidence of unpleasant side effects (which included feeling lethargic, producing too much saliva, and feeling dizzy) was less at low dose compared to standard dose.

Quality of evidence: For main outcomes the quality was low or very low.

Conclusions: We found no evidence that might indicate the best dose of clozapine for patients with schizophrenia. Careful consideration has to be given to balancing the advantages and disadvantages of different doses in relation to weight gain and other side effects. Overall measurements of BMI were similar between groups; however, some side effects appear to be lower at lower doses. Overall, this review highlights the lack of evidence-based information available for addressing the question of what dose of clozapine is most effective with the least side effects. There is a need for large, well-designed and well-reported randomised clinical trials to address this question. There is a particular need for such trials to look at longer-term outcomes, and to examine the effects of clozapine when given at greater than the standard dose.

Authors' conclusions: 

We found no evidence of effect on mental state between standard, low and very low dose regimes, but we did not identify any trials on high or very high doses of clozapine. BMI measurements were similar between groups in the short term, although weight gain was less at very low dose compared to standard dose in one study. There was limited evidence that the incidence of some adverse effects was greater at standard dose compared to lower dose regimes. We found very little useful data and the evidence available is generally of low or very low quality. More studies are needed to validate our findings and report on outcomes such as relapse, remission, social functioning, service utilisation, cost-effectiveness, satisfaction with care, and quality of life. There is a particular lack of medium- or long-term outcome data, and on dose regimes above the standard rate.

Read the full abstract...
Background: 

Schizophrenia and related disorders such as schizophreniform and schizoaffective disorder are serious mental illnesses characterised by profound disruptions in thinking and speech, emotional processes, behaviour and sense of self. Clozapine is useful in the treatment of schizophrenia and related disorders, particularly when other antipsychotic medications have failed. It improves positive symptoms (such as delusions and hallucinations) and negative symptoms (such as withdrawal and poverty of speech). However, it is unclear what dose of clozapine is most effective with the least side effects.

Objectives: 

To compare the efficacy and tolerability of clozapine at different doses and to identify the optimal dose of clozapine in the treatment of schizophrenia, schizophreniform and schizoaffective disorders.

Search strategy: 

We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (August 2011 and 8 December 2016).

Selection criteria: 

All relevant randomised controlled trials (RCTs), irrespective of blinding status or language, that compared the effects of clozapine at different doses in people with schizophrenia and related disorders, diagnosed by any criteria.

Data collection and analysis: 

We independently inspected citations from the searches, identified relevant abstracts, obtained full articles of relevant abstracts, and classified trials as included or excluded. We included trials that met our inclusion criteria and reported useable data. For dichotomous data, we calculated the relative risk (RR) and the 95% confidence interval (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated mean differences (MD) again based on a random-effects model. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE.

Main results: 

We identified five studies that could be included. Each compared the effects of clozapine at very low dose (up to 149 mg/day), low dose (150 mg/day to 300 mg/day) and standard dose (301 mg/day to 600 mg/day). Four of the five included studies were based on a small number of participants. We rated all the evidence reported for the main outcomes of interest as low or very low quality. No data were available for the main outcomes of global state, service use or quality of life.

Very low dose compared to low dose

We found no evidence of effect on mental state between low and very low doses of clozapine in terms of average Brief Psychiatric Rating Scale-Anchored (BPRS-A) endpoint score (1 RCT, n = 31, MD 3.55, 95% CI −4.50 to 11.60, very low quality evidence). One study found no difference between groups in body mass index (BMI) in the short term (1 RCT, n = 59, MD −0.10, 95% CI −0.95 to 0.75, low-quality evidence).

Very low dose compared to standard dose

We found no evidence of effect on mental state between very low doses and standard doses of clozapine in terms of average BPRS-A endpoint score (1 RCT, n = 31, MD 6.67, 95% CI −2.09 to 15.43, very low quality evidence). One study found no difference between groups in BMI in the short term (1 RCT, n = 58, MD 0.10, 95% CI −0.76 to 0.96, low-quality evidence)

Low dose compared to standard dose

We found no evidence of effect on mental state between low doses and standard doses of clozapine in terms of both clinician-assessed clinical improvement (2 RCTs, n = 141, RR 0.76, 95% CI 0.36 to 1.61, medium-quality evidence) and clinically important response as more than 30% change in BPRS score (1 RCT, n = 176, RR 0.93, 95% CI 0.78 to 1.10, medium-quality evidence). One study found no difference between groups in BMI in the short term (1 RCT, n = 57, MD 0.20, 95% CI −0.84 to 1.24, low-quality evidence).

We found some evidence of effect for other adverse effect outcomes; however, the data were again limited.

Very low dose compared to low dose

There was limited evidence that serum triglycerides were lower at low-dose clozapine compared to very low dose in the short term (1 RCT, n = 59, MD 1.00, 95% CI 0.51 to 1.49).

Low dose compared to standard dose

Weight gain was lower at very low dose compared to standard dose (1 RCT, n = 27, MD −2.70, 95% CI −5.38 to −0.02). Glucose level one hour after meal was also lower at very lose dose (1 RCT, n = 58, MD −1.60, 95% CI −2.90 to −0.30). Total cholesterol levels were higher at very low compared to standard dose (1 RCT, n = 58, n = 58, MD 1.00, 95% CI 0.20 to 1.80).

Low dose compared to standard dose

There was evidence of fewer adverse effects, measured as lower TESS scores, in the low-dose group in the short term (2 RCTs, n = 266, MD −3.99, 95% CI −5.75 to −2.24); and in one study there was evidence that the incidence of lethargy (RR 0.77, 95% CI 0.60 to 0.97), hypersalivation (RR 0.70, 95% CI 0.57 to 0.84), dizziness (RR 0.56, 95% CI 0.39 to 0.81) and tachycardia (RR 0.57, 95% CI 0.45 to 0.71) was less at low dose compared to standard dose.

Share/Save