eMJA: Weight gain and diabetes with “second-generation” antipsychotic drugs

Andrew Firestone

Psychiatrist; and Honorary Senior Lecturer, Monash University, Clayton, VIC 3168. afireATtpg.com.au

To the Editor: Emerging evidence suggests that the so-called second-generation antipsychotics (SGAs), especially olanzapine and clozapine, can cause abnormal weight gain and increase the risk of diabetes mellitus.1-3 In Australia, there are calls for a prospective multicentre trial to compare the rates of weight gain and diabetes between SGAs.4,5 The Australian data presented here underline the pressing need for such a study.

Data were examined for the 10-year period January 1994 to December 2003 for:

Total prescriptions dispensed by the Pharmaceutical Benefits Scheme (PBS) and the Repatriation Pharmaceutical Benefits Scheme for 12 antipsychotic drugs; and
Reactions reported in the same period to the Adverse Drug Reactions Advisory Committee (ADRAC) for each of these drugs, involving excessive weight gain or obesity, and diabetes mellitus or hyperglycaemic reactions. Reports were included in the survey only when it was considered that no other drug could be responsible.

As clozapine is dispensed and recorded differently from other SGAs in Australia, complete data on numbers of prescriptions dispensed were not available. However, total Australian expenditure was available for each tablet strength of clozapine for the full 10-year study period, along with number of prescriptions dispensed and costs for the private hospital sector for the 4 years July 2000 to June 2004. Therefore, I calculated the average script cost for each tablet strength, and extrapolated the script numbers for the 10-year period, as shown in Box 1.

Box 2 shows the “report rate” for each SGA for the side effects of weight gain or obesity, and diabetes or hyperglycaemia. The report rate for side effects was greater for clozapine than for any other SGA. Unfortunately, the true situation may be still worse. Clozapine is usually prescribed a month at a time, while the other drugs are prescribed for up to 6 months. Adjusting for this would widen the gap further. Moreover, as ADRAC promotes reporting for new drugs, the report rates for the five drugs introduced during the study period are probably inflated. Clozapine is not one of them.

The limitations of ADRAC data are well known.4 Nevertheless, these are currently our best Australian data and strongly suggest that SGAs, of which risperidone has the most favourable profile, cause weight gain and diabetes much more often than the older antipsychotic agents.

These data accord with previously published studies1 and support the US advice to avoid olanzapine and clozapine if possible. Recent PBS approval in Australia for use of olanzapine in bipolar disorder further underlines the urgent need for a prospective multicentre study to compare weight gain and glucose metabolism in patients taking antipsychotic drugs.

Meanwhile, I suggest that:

Patients who have abnormal weight gain with an SGA might be treated with chlorpromazine, trifluoperazine or haloperidol.
PBS regulation of clozapine might be amended, to discourage its prescription until after failure of a “first-generation” as well as a second-generation antipsychotic drug.

1 Estimation of the total number of clozapine scripts in Australia

Tablet strength (mg)	Private hospitals data (Jul 2000–Jun 2004)			Total clozapine used (Jul 1994–Jun 2004)
Tablet strength (mg)	Total prescriptions	Cost ($)	Average cost/ prescription ($)	Cost ($)	Estimated total prescriptions

25	3 650	230 929	63.27	9 636 814	152 313
50	25	1 443	57.72	85 980	1 490
100	21 057	6 632 499	314.98	153 276 771	486 624
200	69	24 392	353.51	463 131	1 310
Total	24 801	6 889 263	–	163 462 696	641 737

2 Report rates for side effects of antipsychotic drugs

	No. of years*	No. of prescriptions dispensed	No. of ADRAC reports		Report rate (per million prescriptions dispensed)
	No. of years*	No. of prescriptions dispensed	Weight gain^†	Diabetes^‡	Weight gain^†	Diabetes^‡

Chlorpromazine	10	950 221	0	0	0	0
Fluphenazine	10	327 126	0	0	0	0
Trifluoperazine	10	937 605	1	0	1.07	0
Pericyazine	10	657 514	0	0	0	0
Thioridazine	10	1 983 915	1	3	0.50	1.51
Haloperidol	10	1 499 254	2	0	1.33	0
Flupenthixol	9	121 132	0	0	0	0
Zuclopenthixol	8	93 839	0	1	0	10.66
Olanzapine	6	2 786 334	47	19	16.87	6.82
Quetiapine	4	271 957	1	4	3.68	14.70
Risperidone	9	1 298 156	6	2	4.62	1.53
Clozapine	10	641 737§	41	61	63.89	95.05

ADRAC = Adverse Drug Reactions Advisory Committee. * Number of years with data available (as some drugs were introduced only after the start of the 10-year period). ^† Weight gain or obesity. ^‡ Diabetes mellitus or hyperglycaemia. § Estimated number (see Box 1).