Hyperprolactinemia and Antipsychotic Therapy in Schizophrenic Patients with Hashimoto's Thyroiditis.

INTRODUCTION: Hyperprolactinemia (HPRL) is known as a side effect of some antidepressants and antipsychotics. These medicines are common in treatment of schizophrenia. Thus, HPRL is often observed in schizophrenic patients. It is also known that HPRL can occur in Hashimoto's thyroiditis due to prolactoliberin effect of thyroliberin. The clinical pathophysiology of the patients with the comorbidity of schizophrenia and Hashimoto's thyroiditis, receiving antipsychotics, is of special interest. It's fair to assume that these patients have higher risks of HPRL. To analyze risks of HPRL with antipsychotic treatment, to identify an association between the antipsychotic therapy (AT) and HPRL in Hashimoto's patients receiving AT, to explore the association of HPRL and other laboratory parameters in patients with Hashimoto's thyroiditis and schizophrenia during AT. SUBJECTS AND METHODS: We studied 17 patients with HT in comorbidity with schizophrenia receiving AT (mean age 46.5±12.8 years), all euthyroid or with light hypothyroidism. Different laboratory parameters such as anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) antibodies, blood levels of thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3) and prolactin (PRL) were analysed. RESULTS: The study revealed the high levels of PRL, anti-TPO and anti-TG autoantibodies. Thus, patients were classified into 3 groups by the degree of expected HPRL risk from the antipsychotics used: without expected risk, with low and high expected risks. The correlation analysis detected an inverse significant correlation (R=-0.51; p=0.037) between expected level of drug-associated HPRL risk and actual PRL levels in studied group. At the same time, we detected a positive significant correlation between the levels of PRL and FT4 in the groups (R=0.53; p=0.03). The correlations between the levels of PRL and other parameters such as TSH, FT3, anti-TPO, anti-TG, anti-TSH receptor antibodies were not statistically significant. CONCLUSIONS: HPRL in the group was not associated with taking of antipsychotic drugs with high expected HPRL risk. Yet, a significant positive correlation existed between the levels of PRL and FT4. Hence, in Hashimoto's thyroiditis accompanied with treated mental illness there are some non-iatrogenic stimulants of prolactogenesis. It cannot be ruled out that antipsychotics may interfere with prolactin metabolism, which creates a false effect of a positive correlation between prolactin and free thyroxine levels, in contrast to common HPRL of hypothyroidism.

The combined effect of CYP2D6 and DRD2 Taq1A polymorphisms on the antipsychotics daily doses and hospital stay duration in schizophrenia inpatients (observational naturalistic study).

BACKGROUND: To assess the correlation between the antipsychotics (AP) mean daily doses, hospital stay duration and CYP2D6, DRD2 polymorphisms in naturalistic study. SUBJECTS AND METHODS: CYP2D6 polymorphisms *3, *4, *5, *6, *1XN and DRD2/ANKK1 Taq1A polymorphisms were genotyped in a cohort of 226 Caucasian schizophrenic inpatients. AP daily doses, hospital stay duration and AP treatment duration were taken from medical records. To compare mean daily doses of AP among CYP2D6 PMs, EMs, UMs and DRD2/ANKK1 Taq1A carriers the actual AP doses were converted to chlorpromazine (CPZ) equivalents and DDD (defined daily dose). RESULTS: Significant correlation (p=0.004) between CYP2D6 metabolic activity and AP mean daily doses was observed only among DRD2/ANKK1 Taq1A polymorphic allele carriers: 250.53 (95%CI: 154.90-346.17), 473.82 (95%CI: 426.99-520.64) 602.77 (95%CI: 469.65-735.88) CPZ equivalents in PMs, EMs and UMs, consequently. PMs with DRD2/ANKK1 Taq1A CT genotype received significantly lower doses of AP comparing to CC genotype (p=0.02). Mean hospital stay duration of PMs+UMs was significantly higher comparing to EMs (66.4 days (95% CI: 56.9-75.8) vs 50.2 days (95%CI: 45.5-54.7); p=0.047). CONCLUSIONS: In a cohort of schizophrenia inpatients CYP2D6 metabolic activity affects mean AP daily dose only in the presence of DRD2 Taq1A polymorphic allele. CYP2D6 metabolic activity correlates independently from DRD2 Taq1A polymorphism with hospital stay duration. Subpopulation of schizophrenia inpatients with altered CYP2D6 activity (PMs and UMs) carriers of Taq1A polymorphisms needs special attention of clinicians in aligning of AP treatment.

Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial.

Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control). Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.