Metabolic complications of psychotropic medications in psychiatric disorders:Emerging role of de novo lipogenesis and therapeutic consideration

Although significant advances have been made in understanding the pathophysiology of psychiatric disorders(PDs),therapeutic advances have not been very convincing.While psychotropic medications can reduce classical symptoms in patients with PDs,their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes,obesity and non-alcoholic fatty liver disease(NAFLD).The mechanism(s)underlying these metabolic abnormalities is not clear;however,lipid/fatty acid accumulation due to enhanced de novo lipogenesis(DNL)has been shown to reduce membrane fluidity,increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities.Intriguingly,emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity,diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs.In support of this,several adjunctive drugs comprising of anti-oxidants and antiinflammatory agents,that are used in treating PDs in combination with psychotropic medications,have been shown to reduce insulin resistance and development of NAFLD.In conclusion,the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities,and a new avenue for translational research and therapeutic drug designing in PDs.

Disrupted leptin-fatty acid biosynthesis is an early manifestation of metabolic abnormalities in schizophrenia

BACKGROUND Insulin resistance(IR)and impaired energy expenditure(IEE)are irreparable metabolic comorbidities in schizophrenia.Although mechanism(s)underlying IR and IEE remains unclear,leptin and fatty acid signaling,which has profound influence on insulin secretion/sensitivity,glucose metabolism and energy expenditure,could be disrupted.However,no association of plasma leptin with erythrocyte membrane fatty acids,body mass index(BMI),and psychotic symptoms in the same cohort of untreated patients with first-episode psychosis(FEP)or medicated patients with chronic schizophrenia(CSZ)is presented before.These studies are crucial for deciphering the role of leptin and fatty acids in the development of IR and IEE in schizophrenia.AIM To determine the association between plasma leptin,erythrocyte membrane fatty acids,particularly,saturated fatty acids(SFAs),BMI and psychotic symptoms in patients with FEP and CSZ.METHODS In this study,twenty-two drug naive patients with FEP,twenty-one CSZ patients treated with atypical antipsychotic drugs,and fourteen healthy control(CNT)subjects were analyzed.Plasma leptin was measured using sandwich mode enzyme-linked immunosorbent assay.Erythrocyte membrane SFAs were measured using ultrathin capillary gas chromatography.BMI was calculated by using the formula:weight(kg)/height(m^(2)).Psychiatric symptoms were evaluated at baseline using brief psychiatric rating scale(BPRS),and positive and negative syndrome scale(PANSS).The total BPRS scores,positive and negative symptom scores(PANSS-PSS and PANSS-NSS,respectively)were recorded.Pearson correlation coefficient(r)analyses were performed to find the nature and strength of association between plasma leptin,PANSS scores,BMI and SFAs,particularly,palmitic acid(PA).RESULTS In patients with FEP,plasma leptin not BMI was significantly lower(P=0.034),whereas,erythrocyte membrane SFAs were significantly higher(P<0.005)compared to the CNT subjects.Further,plasma leptin showed negative correlation with erythrocyte membrane SFAs-PA(r=-0.4972,P=0.001),PANSS-PSS(r=-0.4034,P=0.028),and PANSS-NSS(r=-0.3487,P=0.048).However,erythrocyte membrane SFAs-PA showed positive correlation with PANSS-PSS(r=0.5844,P=0.0034)and PANSS-NSS(r=0.5380,P=0.008).In CSZ patients,plasma leptin,BMI,and erythrocyte membrane SFAs,all were significantly higher(P<0.05)compared to the CNT subjects.Plasma leptin showed positive correlation with BMI(r=0.312,P=0.032)but not with PANSS scores or erythrocyte membrane SFAs-PA.However,erythrocyte membrane SFAs-PA showed positive correlation with PANSS-NSS only(r=0.4729,P=0.031).Similar changes in the plasma leptin and erythrocyte membrane SFAs have also been reported in individuals at ultrahigh risk of developing psychosis;therefore,the above findings suggest that leptin-fatty acid biosynthesis could be disrupted before the onset of psychosis in schizophrenia.CONCLUSION Disrupted leptin-fatty acid biosynthesis/signaling could be an early manifestation of metabolic comorbidities in schizophrenia.Large-scale studies are warranted to validate the above findings.