With the clinical application of atypical antipsychotic drugs, people are more concerned about the side effects of drugs, especially obesity, cardiovascular abnormalities, abnormal glucose and lipid metabolism, and hyperprolactinemia, which seriously affect the quality of life of patients, and therefore become a hot spot for research. This paper summarizes the current status of domestic and international research on the effects of atypical antipsychotics on serum prolactin and lipid levels as follows: Long Bin, Department of Psychiatry, Shanghai Mental Health Center
Definition of abnormal lipid metabolism and hyperprolactinemia
1 Abnormalities of lipid metabolism The sources of lipids are classified as exogenous and endogenous. Exogenous refers to lipids taken in by food and absorbed into the blood through the digestive system; endogenous refers to those synthesized by liver, fat cells and other tissues and then released into the blood. For some reason, the increase in blood cholesterol (TC) and/ or triglycerides (TG), the increase in low-density lipoprotein (LDL) or the decrease in high-density lipoprotein cholesterol (HDL) are called dyslipidemia in modern medicine. Hyperlipidemia is divided into four categories: A. Hypercholesterolemia: increased serum cholesterol (TC) levels; B. Hypertriglyceridemia: increased serum triglyceride (TG) levels; C. Mixed hyperlipidemia: increased serum cholesterol (TC) and triglyceride (TG) levels; D. HypoHDLemia: decreased serum HDL-C levels. In 1997, China’s “Recommendations for the Prevention and Control of Dyslipidemia” proposed to test four indicators, including TC, TG, LDL-C and HDL-C, and in 2003, the “Recommendations on Clinical Lipid Determination” formulated by the Lipid Expert Committee of the Chinese Medical Association Laboratory Branch The 2002 NCEP ATP III defines the levels of TC, TG, HDL-C and LDL-C as the optimal level, and plasma TC <5.2 mmol/L is the optimal level, and 5.2-6.2 mmol/L is the risk domain value; TG <1.7 mmol/L is the optimal level; HDL-C <1.0 mmol/L is the low level.
Hyperprolactinemia The upper limit of normal prolactin is 15-25 μg/L [1], with an average of 13 μg/L in women and 5 μg/L in men. Prolactin levels > 20 μg/L are called hyperprolactinemia. The adverse effects of hyperprolactinemia usually occur when prolactin levels are > 30-60 μg/L [2 ], mainly manifesting as amenorrhea, breast enlargement and lactation, and loss of libido [3, 4 ]. Prolonged hyperprolactinemia can cause osteoporosis and increase the risk of cardiovascular disease [5 ]. Prolactin levels are higher in the middle and late stages of the menstrual cycle in women; prolactin increases transiently and mildly during meals, stress and sexual activity; prolactin rises 60-90 min after sleep and reaches a peak at 4-7 h in the morning, which is not a biological rhythm because it is only sleep-related and not time-related. The secretion of human prolactin is mainly influenced by neurotransmitters and hormones. Hypothalamic dopamine is released into the pituitary portal vein, which agonizes D2 receptors on the pituitary prolactin cell membrane and inhibits prolactin gene transcription, prolactin synthesis and release. The 5-hydroxytryptamine (5-HT) neurons in the dorsal interstitial nucleus project to the basolateral hypothalamus, releasing 5-HT, agonizing 5-HT1A and 5-HT2A/2C receptors, and promoting prolactin secretion[6 ] . Estrogen inhibits hypothalamic dopamine synthesis and decreases pituitary D2 receptor number, thereby elevating prolactin gene transcription and synthesis [7 ], which enhances basal and stimulated prolactin secretion, while thyrotropin-releasing hormone, antidiuretic hormone, vasoactive intestinal peptide and oxytocin all induce prolactin release, whereas glucocorticoids and thyroxine tend to inhibit prolactin secretion induced by thyrotropin-releasing hormone [ 1 ]. 1].
Effects of atypical antipsychotics on blood lipids
Clozapine is widely used clinically, and its clinical efficacy is relatively certain for both positive and negative symptoms. The serious side effects of clozapine are of great concern, such as obesity and increased body mass, abnormal glucose and lipid metabolism [8-10]. Liu Hongguang [ 11 ] reported that the effect of clozapine on blood lipids was the most significant, and the changes of triglycerides and LDL in female patients were significantly smaller than those in male patients, which was also consistently reported by Tan Chengwen et al [ 12 ]. In China, Liu Sufang et al [13] and Li Hengfen et al [14] reported that low-dose clozapine could cause an increase in TC and TG levels, while high-dose clozapine caused a decrease in HDL and a significant increase in LDL levels, while treatment with high, medium and low dose groups of clozapine could cause a different degree of increase in body mass. The mechanism of occurrence may be that clozapine antagonist H1 causes increased appetite, obesity, insulin resistance, insulin deficiency and elevated blood glucose, causing abnormal fat-islet axis function in the body, and obesity is related to insulin resistance [15-16].
The effect of risperidone on blood lipids has been reported in different studies [ 11-12], He Zhaohui [ 17] showed that there was no significant change in blood lipid level after taking risperidone, which was consistent with the results of Zhou Min et al [ 18] in China. Gao Shuzhen et al [ 19] reported that the effect of risperidone on blood lipids should not be neglected. Another study showed that although the effect of risperidone on blood lipids was not significant, it could cause patients to develop type 2 diabetes [ 20]. Foreign literature reports moderate effects of risperidone on blood lipids and body weight [ 21].
Olanzapine (olanzapine) Jonathan [ 22] showed that olanzapine significantly increased body weight, blood glucose and blood lipids. Another study reported that olanzapine can cause patients to develop type 2 diabetes, and this adverse effect of olanzapine is greater than that of risperidone [ 23], which is consistent with national reports.
Quetiapine (quetiapine) Murad [ 24] et al. divided 56 patients with schizophrenia eligible for DSM-4 into four groups subsequently, risperidone (n = 1 4), olanzapine (n = 1 4), quetiapine (n = 1 4), and clozapine (n = 1 4),comparing body weight, leptin, and triacylglycerol between the four drug groups, and showed that the quetiapine group moderately altered these parameters . In line with the findings of Jonathan [ 22] and Caro JJ et al [ 23].
Ziprasidone and aripiprazole Princetond et al [ 25] conducted a 1-year follow-up study and the results were that patients on ziprasidone and aripiprazole gained only about 1 kg of weight compared to pre-treatment. In agreement with the study by Casey et al [ 26]. Ziprasidone and aripiprazole had almost no effect on blood lipids [ 21].
Effect of atypical antipsychotics on prolactin (prolactin)
Clozapine (clozapine) Clozapine selectively blocks D2 receptors in the midbrain-limbic pathway, but not in the hypothalamic-funnel pathway, and therefore does not elevate prolactin levels while being antipsychotic [4 ]. Meltzer et al. and Goode et al. (1979) reported that clozapine had no or a small effect on prolactin levels in patients with schizophrenia [27-28]. When fluphenazine was replaced by clozapine 400 mg/d for 6 weeks, the prolactin level decreased from 2 times the normal level to the normal range[7] .
Risperidone Risperidone and 9-hydroxyrisperidone both block D2 receptors on the hypothalamic-funnel pathway, causing hyperprolactinemia. Kleinbergdeng et al[ 29] (19999) conducted an 8-week study of risperidone treatment and found that prolactin levels varied greatly before and after treatment and were higher with increasing doses.
Tollefsond et al. [30] (1999) reported that olanzapine caused a mild increase in prolactin levels in patients. The results of domestic studies on the effect of olanzapine on serum prolactin levels are consistent with this [31].
In a study by Small et al [32], quetiapine caused a mild increase in serum prolactin levels, but it was still within the normal range. In China, Peng Daihui et al [33] treated 191 schizophrenic patients with quetiapine or chlorpromazine, and measured serum PRL before and at 8 weeks of treatment, and showed that quetiapine had no effect on serum PRL levels in schizophrenic patients.
Stimmel et al [35] used ziprasidone in the treatment of psychiatric patients. 40 mg/d did not affect prolactin levels, and 160 mg/d only caused a transient increase, which returned to normal when the drug was continued.
Clinical studies have found that aripiprazole has antagonistic effects on D2 receptors in the midbrain-limbic pathway, partial agonism in the midbrain cortical region, agonist-antagonist effects on D2 neurons in the midbrain periaqueductal region, and inhibition of nigrostriatal DA pathway transmission. that found no significant changes in serum prolactin levels before and after aripiprazole treatment.
Some atypical antipsychotics cause elevated lipid and serum prolactin levels in patients, but those at risk for abnormal lipid and serum prolactin levels should not be overlooked in clinical work. Obese and diabetic individuals are at high risk for developing dyslipidemia. Women, pregnant women, children and adolescents are more likely to have increased serum prolactin levels [37]. As the side effects of antipsychotic drugs seriously affect the quality of life and occupational functioning of patients, both mental health workers or patients and their families are looking forward to newer antipsychotic drugs that are more therapeutic and safer.