Background
Hyperprolactinemia (HPRL) and glucose and lipid metabolism abnormalities are often found in patients with schizophrenia and are usually considered secondary to the use of antipsychotic drugs [
1‐
4]. The production of prolactin (PRL) is inhibited by dopamine release in the hypothalamo-pituitary circuit and can be increased by blocking type 2 (D2) dopamine receptors [
5]; therefore HPRL in patients with psychosis seems to be related mainly to the D2-receptors affinity of antipsychotic drugs [
6]. Moreover, second generation antipsychotics (SGAs) have a marked propensity to induce increased levels of blood glucose, glycosylated hemoglobin and insulin, higher IR, alterations of blood lipid profiles, weight gain and sometimes frank diabetes mellitus (T2DM) [
7‐
9]. The focus of these metabolic abnormalities is on the phenomena of hyperglycemia and IR, but the mechanism through which SGAs induce glucose metabolism disorders is not clearly understood and is likely multifactorial [
3].
In more recent years it’s been purposed that HPRL and impaired glucose tolerance may be independent of antipsychotic treatment, at least in a subgroup of patients with psychotic disorders. Some authors have identified variations in PRL secretion in drug-free patients, suggesting that schizophrenia itself may be characterized by an abnormal regulation of PRL levels [
5,
10‐
13]. Likewise some studies showed that antipsychotic naive patients with first episode psychosis (FEP) had increased prevalence of impaired glucose tolerance and were more insulin resistant than their healthy comparison subjects [
14‐
16]. These findings lead to the hypothesis that schizophrenia spectrum psychosis is implicated in the pathophysiology of diabetes [
15] although conflicting data on the risk of T2DM in patients with schizophrenia prior to antipsychotic treatment has been published [
17,
18].
In this study we moved from the hypothesis that at least a subgroup of patients with schizophrenia spectrum psychosis may have a specific vulnerability for abnormalities of regulation of PRL secretion and impaired glucose tolerance, independent of antipsychotic treatment. We purposed that HPRL and abnormalities of glucose and lipid metabolism parameters may be related to the acute phase of psychosis. To verify this hypothesis we compared PRL levels, glycometabolism parameters and lipid profile between a sample of drug-naive adolescents in the acute phase of FEP and a control group of subjects at clinical high risk (CHR) of developing psychosis, age and sex matched.
Discussion
The main findings of this study were significantly higher values of PRL and HOMA-IR in the sample of early onset drug-naive FEP when compared with subjects at CHR of developing psychosis. These data suggested that dysfunctions of regulation of PRL serum levels and abnormalities of glucose metabolism parameters could be related to acute phase of FEP more than to a clinical risk of psychotic illness, excluding the iatrogenic effects of antipsychotic drugs.
Some previous studies on patients with adult onset FEP showed that HPRL may be a condition pre-existing the introduction of antipsychotic drugs, at least in a subgroup of cases [
10‐
13]. In addition genetic studies suggested that some patients with schizophrenia may have a predisposition to HPRL consisting in functional − 1449 g/t polymorphism of the PRL gene [
26,
27]. In a review on the literature of the relationship between PRL and schizophrenia Rajkumar R.P. recommended a reappraisal of the role of prolactin in the various stage of schizophrenia, particularly with regard to its onset [
5]. At this purpose an important concern involves the relationship between stress, psychosis onset and increased release of PRL. As is known acute stress leads to an increased serum level of PRL [
28] and, in addition to it, patients with FEP report more stressful life events and perceived stress when compared to healthy subjects [
29]. An increased level of PRL triggers dopamine release by a feedback mechanism, therefore it is reasonable to infer that patients with schizophrenia may have an exaggerated PRL response to stress mediated by a dysfunction in dopaminergic transmission [
5]. Moreover, it has been hypothesized that in early psychosis a stress related hormonal dysregulation leads to a greater activation of the hypothalamic-pituitary-adrenal axis (HPA) with an increase in the number and size of corticotroph cells [
30,
31]. The pituitary gland is a dynamic structure changing in response to different conditions. Nordholm et al. published a systematic review and meta-analysis on pituitary gland volume showing that the onset of psychosis, more than the high-risk state, is associated with an enlargement of the pituitary gland and that this is independent of antipsychotics [
30]. On the other hand, pituitary size may be influenced by age and gender [
32], so that subjects in juvenile age (puberal and post-puberal stage) and female in gender may be more easy to have an increase of pituitary gland volume and activation during the early stage of psychosis [
32,
33]. All these evidences give more consistency to our finding of HPRL in acute phase of FEP more than in CHR subjects, so we suggest that neurobiological abnormalities related to the acute phase of full emergence of psychotic symptoms in adolescent patients may be involved in dysregulation of PRL secretion. Considering the development and sexual dimorphism of the pituitary gland, further studies could be useful to examine the relevance of age and gender differences on early onset psychiatric disorders in which pituitary dysfunctions has been implicated. In addition, the early identification of HPRL in drug naïve adolescents with FEP may be useful in clinical setting to guide treatment decisions and to manage antipsychotic drugs over the time.
A complex and multifactorial relationship it’s been purposed also to explain the risk of diabetes in psychotic disorders [
2]. In a recent meta analysis examining data of glucose tolerance, insulin and insulin resistance from drug naïve adult patients with non affective psychosis (mean age of 28.7) Greenhalgh et al. purposed that an increased risk of diabetes may be apparent in acute phase of psychosis prior to antipsychotic use. The authors found that at the time of first clinical contact for psychosis, patients have a slight increase in fasting glucose, which most of them maintain in the normal range, despite a small increase in IR, by secreting additional insulin [
34]. According to these evidences, we found a higher fasting glucose in the FEP group then in the CHR group, with no clinical significance, as the mean values for both groups were within normal range. The mean value of HbA1c, reflecting the average plasma glucose, was within normal range for both groups too, so we can assume that the statistical difference (HbA1c was higher in the CHR group than in the FEP group) was not of clinical significance. Actually, some previous studies showed that determination of fasting plasma glucose or HbA1c is not very useful in the screening of impaired glucose tolerance [
35,
36]. Conversly Garcia-Rizo et al. have recently suggested that at the onset of psychosis HOMA-IR may be considered a more useful predictor of cardiometabolic risk than other metabolic syndrome criteria [
37]. The HOMA-IR is a proxy estimate of IR, based upon the relationship between fasting glucose and insulin levels, with higher value of HOMA-IR representing more severe IR [
38]. Several authors have recently purposed a definition of HOMA-IR values across the age continuum from childhood to adolescence, identifying IR with more specificity and sensibility [
39,
40]. Actually, there is no consensus regarding the reference value of HOMA-IR for the diagnosis of IR in the pediatric age group and several cut off points have been reported in the literature according to age, gender, pubertal status and BMI [
38,
41,
42]. The most used cut off value is 3.16 for obese children, considering that in obese young individuals IR may exceed physiological values especially at the time of puberty [
24,
25,
41]. Different population-based studies in the world on normal weight healthy children and adolescents found that a HOMA-IR ≥ 2.6 was associated with a greater cardiovascular and metabolic risk [
38,
43,
44]. According to these data we can assume that the mean value of HOMA-IR of 3.07 we found in the FEP group was indicative of IR, since the BMI of these patients was in the range of normal weight. So we suggest that since adolescence, as up to now purposed for adulthood [
34], a higher risk of impaired glucose homeostasis, assessed by an increase in HOMA-IR, may be evident in the acute phase of FEP, also in absence of other risk factors as overweight and independently by antipsychotic intake. This is of substantial clinical importance to identify adolescent patients with FEP at increase cardiovascular risk, in order to implement preventive strategies and optimize therapies to reduce the burden of weight gain relate to antipsychotic drugs.
We reserved one last comment to the hypothesis of a deep relationship between HPRL and IR in schizophrenia spectrum psychosis. In a 2016 review Gragnoli et al. suggested that in schizophrenic patients neuroendocrine dysfunctions involving dopamine-prolactin pathway might contribute to both diabetes and schizophrenia [
45]. This hypothesis recalls the multifunctional role of PRL that, beside the lactogenic activity, has different functions broadly classified as reproductive, metabolic, osmoregulatory and immunoregulatory [
46]. As “metabolic hormon” increasing evidence showed that PRL has different effects on glucose metabolism and may be involved in the manifestation of IR [
47,
48]. On the other hand we know that IR is not an endocrine disorder per se but more a disorder of several systems that appears in many inflammatory conditions with an activated immune/repair system and/or in different conditions with increased mental activation via stress axes [
49,
50]. So Gragnoli et al. purposed that PRL and/or PRLreceptor gene may carry risk variants associated with schizophrenia, T2DM and/or their clinical association [
45]. This hypothesis is in line with a contemporary conceptual model of schizophrenia as a complex disorder with several manifestations outside the brain, so that some “non-psychiatric” abnormalities, traditionally considered as “comorbid” conditions, actually appear as integral parts of the illness, sharing etiopathophisiological factors [
51] (Brian Kirkpatrick 2015). In this framework we can suggest that our finding of co-occurring HPRL, increase in HOMA-IR and psychotic symptoms may be considered different manifestations of the acute phase of psychotic onset with a common neurobiological vulnerability.
Some limitations need to be considered. Certainly the small sample size of this study limited the statistical power of the results and made difficult to evaluate the effect of age, sex, pubertal stage, phase of disease on neuroendocrine and metabolic parameters. We must consider, in addition, that this is a cross-sectional study. Further replications trough longitudinal studies including larger samples would be needed to a better understanding of the relationship between schizophrenia spectrum psychosis, regulation of prolactin secretion and IR, according to different age of onset and different stage of disease.