Influence of antipsychotic drugs on hormone levels

The aim of the studies summarized in this thesis was to investigate the influence of antipsychotic drugs on hormone levels, in order to identify causes of hormonally related side effects of these drugs. The effect of antipsychotics on the prolactin (PRL) secretion, the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis and the glucose-insulin homeostasis was studied. In all 106 patients, diagnosed with schizophrenia or related psychoses according to DSM-III-R or DSM-IV, and on long-term treatment with classical antipsychotics (n=77), clozapine (n=15) or olanzapine (n=14). were examined. Fasting blood samples for PRL, GH, GH-dependent IGF-I, insulin, glucose, lipids, leptin and antipsychotic drug serum concentrations were analyzed. In addition, body mass index (BMI) was calculated. A slight to moderate degree of hyperprolactinemia was found in one third of patients on long-term treatment with classical antipsychotics. Despite lower dosages of antipsychotics in women, hyperprolactinemia was more common in women compared to men, indicating a sex-related difference in the sensitivity to antipsychotics in the hypothalamic-pituitary PRL-regulation.

In total 53 (68 %) of 78 patients on treatment with antipsychotic drugs (classical agents, clozapine, olanzapine) had elevated BMI >25. Patients receiving clozapine had a lower level of GH-dependent IGF-I than patients receiving classical antipsychotics or olanzapine, pointing to a lower GH secretion in clozapine-treated patients. As GH deficiency causes weight gain, a possible down-regulated GH secretion might be a contributive factor to weight gain during clozapine therapy. Olanzapine-treated patients had a significantly higher serum insulin level compared to classical antipsychotic- treated patients, despite similar BMI, pointing to a probable influence of olanzapine on insulin secretion. In clozapine-treated patients the insulin levels correlated to the drug serum concentration, indicating a likely influence also of clozapine on insulin secretion.

The gender difference in leptin levels, i.e. females having higher levels than males, was found in patients receiving classical antipsychotics, but not in patients receiving clozapine or olanzapine, suggesting that the leptin regulation is altered during clozapine and olanzapine treatments. The influence of clozapine and olanzapine on both insulin and leptin levels may be associate with these agents' weight-gain inducing ability. The majority of the olanzapine-treated patients (10/14) had signs of the metabolic syndrome, with insulin resistance, hyperlipidemia and/or overweight. Therefore, patients on long-term treatment with antipsychotics, especially olanzapine, ought to be evaluated regarding this syndrome. In conclusion, antipsychotic drugs have a complex influence on hormonal secretion. However, with increased knowledge of the hormonal changes caused by these drugs, the future value of antipsychotic medication will be enhanced.

List of scientific papers

I. Melkersson K, Hulting A-L, Hall K (1999). Hormonal evaluation in schizophrenic patients treated with neuroleptics. Neuroendocrinology Letters. 20(3-4):199-200.
https://pubmed.ncbi.nlm.nih.gov/11462115

II. Melkersson K, Hulting A-L, Rane A (2000). Gender differences in dose requirement and prolactin elevation of antipsychotics in patients with schizophrenia or related psychoses. Br J Clin Pharmacol. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/11318766

III. Melkersson KI, Hulting AL, Brismar KE (1999). Different influences of classical antipsychotics and clozapine on glucose-insulin homeostasis in patients with schizophrenia or related psychoses. J Clin Psychiatry. 60(11):783-791.
https://pubmed.ncbi.nlm.nih.gov/10584769

IV. Melkersson KI, Hulting AL, Brismar KE (2000). Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. J Clin Psychiatry. 61(10):742-749.
https://pubmed.ncbi.nlm.nih.gov/11078035

V. Melkersson K, Hulting A-L (2001). Insulin and leptin levels in patients with schizophrenia or related psychoses-a comparison between different antipsychotic agents. Psychopharmacology. 154(2):205-212.
https://pubmed.ncbi.nlm.nih.gov/11314683

VI. Melkersson K, Khan A, Hilding A, Hulting A-L (2001). Different effects of antipsychotic drugs on insulin release in vitro. [Submitted]