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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 pharmacistsworking 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


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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 in8 out of 35 psychiatric inpatients.10 Osteoporosis in schizophrenia is under-

researched 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 femaleschizophrenic 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 andendometrial cancer, other cancers including breast and prostate cancer, respiratory


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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 self-

esteem, 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 somecaution - 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 short-

term 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


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Table 1: Somnolence with olanzapine, risperidone and quetiapine

Adapted from reference 18

Drug / daily dose % of patients

reporting

somnolence

Number needed

to harm (NNH)

95% Confidence

Interval

Placebo 16 -Olanzapine 5mg

(+/- 2.5mg)

20 25 6 to infinity

Olanzapine 10mg

((+/- 2.5mg)

30 7 4 to infinity

Olanzapine 15mg

(+/- 2.5mg)

39 4 3 12

Placebo 1 -

Risperidone


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References


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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. CNS Drugs 1998; 10: 209-222

5 Korbonits M, Grossman AB. Drug-induced hyperprolactinaemia.Prescribers Journal 2000; 40: 157-164

6 Ataya K, Mercado A, Kartaginer J et al. Bone density and reproductive hormones in patients with neuroleptic-induced hyperprolactinaemia.Fertil Steril 1988; 50: 876-81

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.

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16 von Bardeleben U, Benkert O, Holsboer F. Clinical and neuroendocrine effects of zotepine a new neuroleptic drug. Pharmacopsychiatry 1987;20:28-34

17Otani K, Kondo T, Ishida M et al. Prolactin response to zotepine in schizophrenic patients. Human Psychopharmacology 1993;8:35-39

18Physicians Desk Reference. Medical Economics Co Inc 2002. http://www.pdrel.com

19Willett 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

22Stanton JM. Weight gain associated with neuroleptic medication: a review.

Schizophrenia Bulletin 1995; 21; 463-472

23Colonna 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

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

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

26Brecher 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

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28 Zoleptil Summary of Product Characteristics, November 2001.
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