NICE and atypical antipsychotics the forgotten side effects

The recent guidance from the National Institute for Clinical Excellence (NICE) on the use of atypical antipsychotics in schizophrenia was a breath of fresh air to this area of therapeutics and will have been welcomed by most psychiatrists and pharmacists working with patients with schizophrenia. Many will have been frustrated at local arrangements to limit the use of atypical antipsychotics because of their cost when other areas seemed more liberal in their use. Where the guidance from NICE contains surprises is in its omissions. Certainly, key patient groups are covered: first-episode patients, chronic schizophrenia, patients in relapse, and patients with refractory schizophrenia. However, although NICE identified a number of key side effects considered to be distressing by patients, its guidance is based solely on one aspect of adverse effects: drug-induced movement disorders. What about the other side effects? According to NICE, patients with schizophrenia consider the most important side effects to be extrapyramidal symptoms (EPS), sexual dysfunction, weight gain, and sedation.1 However, all but EPS are subsequently ignored. Pharmacists working with patients taking antipsychotics will be only too aware of the impact these other adverse effects can have in terms of causing distress, impairing quality of life, contributing to stigma, and having an adverse impact on acceptance of treatment. It seems appropriate then, to review atypical antipsychotics in relation to these other side effects. Since there is no effective alternative to clozapine in refractory schizophrenia, clozapine will not be included in the review.

Effects on prolactin and sexual health

The effects of conventional antipsychotics on prolactin are well known. Over 25 years ago, the sustained elevation of serum prolactin to pathological levels by conventional antipsychotics was demonstrated by Meltzer and Fang.2 The most important factor regulating prolactin is the inhibitory control exerted by dopamine. Any agent that blocks dopamine receptors in a non-selective manner can cause elevation of serum prolactin. The most common clinical effects of hyperprolactinaemia are: in women; anovulation, infertility, amenorrhoea, decreased libido, gynaecomastia, and galactorrhoea. In men; decreased libido, erectile or ejaculatory dysfunction, azoospermia, gynaecomastia, and (occasionally), galactorrhoea. 3,4 Less frequently, hirsutism in women, and weight gain have been reported.4,5 Sexual function is a complex area that includes emotions, perception, self-esteem, complex behaviour and the ability to initiate and complete sexual activity. Important aspects are the maintenance of sexual interest, the ability to achieve arousal, the ability to achieve orgasm and ejaculation, the ability to maintain a satisfying intimate relationship, and self-esteem. The impact of antipsychotics on sexual functioning is difficult to evaluate, and sexual behaviour in schizophrenia is an area in which research is lacking. Data from short-term clinical trials may greatly underestimate the extent of endocrine adverse events. There is convincing evidence that prolactin elevation is associated with reductions in

bone mineral density though most of the evidence comes from non-psychiatric populations. There have been several reports of decreased bone mineral density in psychiatric populations, though risk factors in addition to hyperprolactinaemia were also present, including cigarette smoking, lack of exercise, and poor diet.6,7,8 Reductions in bone mineral density have been reported in both male and female psychiatric patients,9,10 and Halbreich and co-workers found compression fractures in 8 out of 35 psychiatric inpatients.10 Osteoporosis in schizophrenia is underresearched but should, perhaps, receive greater attention given the aging psychiatric population and the availability of new prolactin-sparing antipsychotic agents. Concerns have also been raised that hyperprolactinaemia may increase the risk for breast cancer, but in psychiatric populations, cigarette smoking or alcohol abuse may also increase the risk, and large epidemiological studies are needed to determine the actual level of risk with antipsychotic-induced hyperprolactinaemia.11,12 However, given the degree of concern, women taking conventional antipsychotics should undergo regular breast screening.13 A systematic review of excess mortality of mental disorders found that there was an excess risk of death from breast cancer in female schizophrenic patients (Standardised Mortality Ratio 115, 95% CI 106-125).14 The authors were not able to explain this finding but speculated that it may have been an outcome of reduced fertility.14 Atypical antipsychotics are also known to contribute to the development of hyperprolactinaemia. Amisulpride is similar to conventional antipsychotics in its propensity to elevate serum prolactin, and at doses >600mg/day has an incidence of endocrine adverse events similar to that of haloperidol at doses of 15-20mg/day.15 Data for zotepine are limited, but suggest a dose-related increase in prolactin levels.16,17 Data for olanzapine, quetiapine and risperidone are published in the Physicians Desk Reference (PDR); a useful reference source since it reports incidence rates for most adverse effects, including EPS, weight gain, and somnolence.18 The PDR states that olanzapine elevates prolactin levels, and a modest elevation persists during chronic administration. The following adverse effects are listed as frequent: decreased libido, amenorrhoea, metrorrhagia, vaginitis.18 For quetiapine, the PDR states, an elevation of prolactin levels was not demonstrated in clinical trials, and no adverse effects relating to sexual dysfunction are listed as frequent.18 The PDR states that risperidone elevates prolactin levels and the elevation persists during chronic administration. The following adverse effects are listed as frequent: diminished sexual desire, menorrhagia, orgastic dysfunction, and dry vagina.18

Effects on weight
The physical and psychological consequences of weight gain and obesity are well known. The health risks of excess weight are the same for those with a mental illness and the general population: an increase in weight of only 5 kg may significantly increase the risk of heart disease.19 Obesity is associated with increased risk of developing physical illnesses including hypertension, stroke, angina, increased mortality from coronary artery disease, type II diabetes, gallbladder disease, osteoarthritis, gynaecological complications including menstrual irregularity and endometrial cancer, other cancers including breast and prostate cancer, respiratory

problems, sleep apnoea, and reduced life expectancy.20 Patients with schizophrenia appear to be at particular risk for obesity-related conditions like cardiovascular disease and type II diabetes.21 Substantial weight gain may also adversely affect selfesteem, social functioning and physical activity, and may be an important impediment to social integration among those whose social skills are already often diminished.22 The most comprehensive review of short-term weight change with antipsychotics is the meta-analysis by Allison et al, of 81 acute studies of antipsychotic agents where weight changes were reported.21 Where data were available, weight changes after ten weeks of treatment at a standard dose were estimated. Among the classical antipsychotics, low potency agents such as thioridazine and chlorpromazine caused the most weight gain with mean increases of 3.49kg and 2.1kg respectively, while high potency agents like haloperidol and fluphenazine caused the least weight gain with increases of 0.48kg and 0.43kg respectively. Mean increases for newer antipsychotics were: clozapine 3.99kg, olanzapine 3.51kg, risperidone 2.0kg. Data were not presented for amisulpride, quetiapine, or zotepine. Because the data show weight gain extrapolated to ten weeks, these results should be interpreted with some caution - weight gain may continue after the acute treatment phase and may not plateau until after several months or even longer have passed.21 A long-term safety study of amisulpride found that 32% of amisulpride-treated patients (n=370, mean dose 605mg/day at endpoint) gained more than 5% of their baseline weight compared with 18% of haloperidol-treated patients (n=119, mean dose at endpoint 14.6mg/day).23 As with neuroendocrine effects, data for zotepine are limited, but a retrospective study in 110 zotepine-treated patients found a significantly greater weight gain with zotepine than with conventional antipsychotics: 41% of patients gained 2-5kg, and 27% gained over 5kg.24 A second retrospective study found a greater increase in weight with zotepine (n=19) than with clozapine (n=29) with mean weight gains of 4.3kg and 3.1kg respectively.25 Data on the effects on weight of olanzapine, quetiapine and risperidone are reported in the PDR. In shortterm trials, weight gain was reported by 6% of olanzapine-treated patients compared with 1% on placebo; 2% of quetiapine-treated patients compared with 0% on placebo; and less than 1% of risperidone treated patients.18 In the long-term, 56% of olanzapine-treated patients gained more than 7% of their baseline weight with an average weight increase of 5.4kg.18 Long-term data for quetiapine and risperidone are not reported in the PDR, but data for quetiapine suggest a low propensity for weight gain in long-term treatment.26

Atypical antipsychotics and sedation

Sedation with amisulpride occurs in less than 5% of patients.27 For zotepine, somnolence occurs in more than 10% of patients,28 and in one study was reported by 74% of patients, persisting for over 2 weeks.16 Data from the PDR relating to somnolence for olanzapine, quetiapine and risperidone are shown in Table 1. As can be seen, somnolence is very common with olanzapine and occurs in a dose-related fashion.18 Somnolence also occurs in a dose-related fashion with risperidone, though it is much less common than with olanzapine.18 Somnolence is also common with quetiapine, though it appears not to be dose-related.18

Table 1: Somnolence with olanzapine, risperidone and quetiapine Adapted from reference 18 Drug / daily dose % of patients Number needed 95% Confidence reporting to harm (NNH) Interval somnolence Placebo 16 Olanzapine 5mg 20 25 6 to infinity (+/- 2.5mg) Olanzapine 10mg 30 7 4 to infinity ((+/- 2.5mg) Olanzapine 15mg 39 4 3 12 (+/- 2.5mg) Placebo Risperidone </= 10mg Risperidone 16mg Placebo Quetiapine 1 3 8 11 18 50 14 14 20 to infinity 8 50 8 - 92

Conclusion
On measures of hyperprolactinaemia and effects on sexual health, effects on weight, and somnolence, there are important differences in the side-effect profiles of atypical antipsychotics. The Guidance from NICE states that decisions over which atypical should be used for an individual patient should be based on an informed discussion of proposed treatments and their side effect profiles. Pharmacists need to develop the means to ensure that patients make their choices on the basis of relevant credible accurate information, and not on the vague utterances that are heard all too often when patients raise questions concerning their medicines.

References

1 National Institute for Clinical Excellence. Guidance on the use of newer (atypical) antipsychotic agents for the treatment of schizophrenia. June 2002. 2 Meltzer HY, Fang VS. The effect of neuroleptics on serum prolactin in schizophrenic patients. Archives of General Psychiatry 1976; 33: 279-86 3 Duncan D, Taylor D. Treatment of psychotropic-induced hyperprolactinaemia.
Psychiatric Bulletin 1995; 19: 755-7

4 Hamner MB, Arana GW. Hyperprolactinaemia in antipsychotic-treated patients: guidelines for avoidance and management. 5 Korbonits M, Grossman AB. Drug-induced hyperprolactinaemia.
Prescribers Journal 2000; 40: 157-164

CNS Drugs 1998; 10: 209-222

6 Ataya K, Mercado A, Kartaginer J et al.

Fertil Steril 1988; 50: 876-81

Bone density and reproductive hormones in patients with neuroleptic-induced hyperprolactinaemia

7 Abraham G, Friedman RH, Verghese C, de Leon J.

Osteoporosis and schizophrenia: can we limit known risk factors? Soc Biol Psychiatry 1995; 38: 2

8 Halbreich U, Palter S. Accelerated osteoporosis in psychiatric patients: possible pathophysiological processes. Schizophrenia Bulletin 1996; 22: 447-54 9 Baastrup PC, Christiansen C, Transbol I. Calcium metabolism in schizophrenic patients on the long-term neuroleptic therapy. Neuropsychobiology 1980; 6: 56-59 10 Halbreich U, Rojansky N, Palter S. Decreased bone mineral density in medicated psychiatric patients. Psychosom Med 1995; 57: 485-91 11 Wang DY, Stepniewska KA, Allen DS et al. Serum prolactin levels and their relationship to survival in women with operable breast cancer.
J Clin Epidemiol 1995; 48: 959-68

12 Halbreich U, Shen J, Panaro V. Are chronic psychiatric patients at increased risk for developing breast cancer? 13 Dickson RA, Glazer WM. Neuroleptic-induced hyperprolactinaemia.
Schizophrenia Research 1999; 35(Suppl): S75-S86

American Journal of Psychiatry 1996; 153: 559-60

14 Harris EC, Barraclough B.

Excess mortality of mental disorder

British Journal of Psychiatry 1998; 173: 11-53

15 Coukell AJ, Spencer CM, Benfield P. Amisulpride: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of
schizophrenia. CNS Drugs 1996;6:237-256

16 von Bardeleben U, Benkert O, Holsboer F. 17 18

Clinical and neuroendocrine effects of zotepine a new neuroleptic drug. Pharmacopsychiatry 1987;20:28-34

Otani K, Kondo T, Ishida M et al. Prolactin response to zotepine in schizophrenic patients. Human Psychopharmacology 1993;8:35-39

Physicians Desk Reference. Medical Economics Co Inc 2002.

http://www.pdrel.com

19
Willett WC, Manson JE, Stampher MJ et al. Weight, weight change, and coronary heart disease in women: risk within the normal weight range. JAMA 1995; 273: 461-465

20 Rockwell WJK, Ellinwood EH, Trader DW. Psychotropic drugs promoting weight gain: health risks and treatment implications. South Med J 1983; 76: 1407-1412 21 Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156: 1686-96 22
Stanton JM. Weight gain associated with neuroleptic medication: a review. Schizophrenia Bulletin 1995; 21; 463-472

23
Colonna L, Saleem P, DondeyNouvel L et al. Long-term safety and efficacy of amisulpride in subchronic or chronic schizophrenia. International Clinical Psychopharmacology 2000;15:13-22

24
Wetterling T, Mussigbrodt H. Gewichtszunahme: eine nebenwirkung von zotepin? Nervenartz 1996;67:256-261

25
Wetterling T, Mussigbrodt H. Weight gain: side effect of atypical neuroleptics? Journal of Clinical Psychopharmacology 1999;19:316-321

26
Brecher M, Rak IW, Melvin K, Jones AM. The long-term effect of quetiapine (Seroquel) monotherapy on weight in patients with schizophrenia. Int J Psychiatry Clin Pract 2000; 4: 287-291

27 Electronic Medicines Compendium 2002. http://emc.vhn.net/professional/ 28 Zoleptil Summary of Product Characteristics, November 2001.