Metabolic syndrome in schizophrenia: theoretical, clinical and translational perspectives.

Metabolic syndrome in schizophrenia is in many ways, an epitome of the mind-body monism of modern psychiatry and medicine. The focus of this interaction has evolved over the last two decades from the viewpoint that this adverse-effect as mere collateral damage due to the newer antipsychotics’ pharmacodynamic profile to a perspective that metabolic dysregulation might have complex and intrinsic link to schizophrenia pathogenesis. Interestingly, this association was indeed alluded to much earlier in Maudsley's work,[1] long before atypical antipsychotics came into clinical practice. Metabolic syndrome adds significantly to the morbidity of schizophrenia and is an important cause of mortality in this population.[2] In contemporary psychiatry, apart from significant clinical implications, the association between schizophrenia and metabolic syndrome has provided a fertile ground for etiological hypothesis generation and testing and has the potential toward facilitating the emergence of newer therapeutics.[3]

Studies have demonstrated that antipsychotic-naïve patients as well as relatives of patients with schizophrenia have impaired glucose tolerance and increased insulin resistance compared with the normal controls.[45] An exciting development in the last few years has been the paradigm shift in understanding metabolic disorders consequent to antipsychotic use. A rapidly growing evidence base, although not unequivocal, supports the hypothesis that metabolic side-effects might be intrinsically linked to the efficacy of antipsychotic medication[6] and that without these side-effects, one may not have any effects either.[78] Several common genetic and environmental risk factors have putatively been linked with increased risk of both schizophrenia and diabetes, which add an extra layer of complexity in understanding the interactions between these two disorders. Pathophysiological links between schizophrenia (a predominantly dopamine related condition) and metabolic diseases such as obesity, diabetes and hypertriglyceridemia (predominantly insulin related conditions) has been strengthened by independent lines of enquiry as demonstrated in recent studies. Replication of the shared genetic risk between schizophrenia and diabetes in two unrelated population samples,[910] both implicating the Transcription factor 7-like 2 (TCF7L2) gene (a gene that has been most consistently replicated in the risk toward type-2 diabetes mellitus[11]) have added substance to a link that was long suspected. That the gene product interacts closely with β-catenin,[12] a member of the Wnt pathway, which has been shown to be dysregulated in patients with schizophrenia, further underscores the biological significance of the finding. The expression of the β-catenin gene itself has been shown to be decreased in patients with schizophrenia.[13] The Wnt pathway is involved in cell proliferation and differentiation. Abnormalities in this pathway have been cited as evidence backing the neurodevelopmental theory of schizophrenia. Other members of the pathway like glycogen synthase kinase 3β (GSK3β) have direct interactions with Disruptedin schizophrenia 1, genetic abnormalities in which, consistently come up in an assessment of the genetic risk factors for schizophrenia.[14] GSK3β has further been shown to be involved in mediation of dopamine action and responds to antipsychotic drugs.[6]

Interestingly, GSK3β influences inflammatory pathways[15]– for example, the ones that involve Toll-like receptors,[16] which are implicated in schizophrenia pathogenesis.[17] This link is significant given the importance of immune-inflammatory aberrations of possible prenatal origin that connects schizophrenia and metabolic syndrome. Prenatal immune activation, due to various kinds of prenatal adversity has been shown to be associated with increase rates of both schizophrenia as well as diabetes.[18] Barker's hypothesis, that malnourishment during critical gestational epochs alters the function and structure of organs, perhaps permanently, but that the effects of this may not be apparent for several years,[19] helps explain how these two, apparently unrelated diseases (schizophrenia and diabetes mellitus), might have a shared pathogenesis secondary to fetal programming aberrations.[20]

In addition to these intriguing theoretical perspectives, the high prevalence of metabolic syndrome in schizophrenia and its negative effect on the life expectancy emphasizes the need for handling metabolic syndrome in a proactive and thorough manner in contemporary clinical psychiatry.[21] Metabolic syndrome adversely impacts the quality-of-life[22] and its association with other complications like obstructive sleep apnea syndrome further add to the clinical burden. Various factors including lack of knowledge among physicians, patients’ and caregivers’ attitude toward an increase in weight and often difficult clinical situation act as barriers to implement effective interventions to ameliorate this challenging co-morbidity.[23] The importance of intensive monitoring and early intervention, therefore, cannot be overemphasized.[24] Using the lowest effective dose of antipsychotic, healthy life-style advice and judicious switching between antipsychotics are considered as the most commonly used strategies to handle metabolic complications. Nonetheless, clinicians are, oftentimes, caught between the devil and the deep blue sea when the offending drug has proven to be the most effective in ensuring control of psychotic symptoms. Apart for optimizing the choice as well as the dose of antipsychotics, various add-on medication options are available to treat metabolic syndrome in schizophrenia. For instance, metformin[25] and topiramate[26] have been used quite a lot and often successfully in the management of metabolic problems. The consistency of their efficacy, however, is moderate at best. Recently, approved drugs and combinations such as lorcaserin and topiramate-phentermine combination may help widen the narrow pharmacological repertoire available to a clinician.[27] Interestingly, micronutrients, especially vitamin B12, have been shown to be involved in mediation between insulin resistance and inflammation.[28] Investigating for and correcting vitamin B12 deficiency in those who develop metabolic side-effects may prove useful. In addition, there is preliminary evidence for use of immune modulators like minocycline, which may help in the treatment of metabolic complications as well as cognitive and negative symptoms of schizophrenia.[293031] A healthy balance and prioritization of management issues – symptom control vis-à-vis decreasing the side-effect burden along with an open discussion involving the patient and caregivers often facilitates effective management.[32]

However, it is important to be mindful that these pharmacological strategies need to be complemented with adequate life-style changes like diet management and regular physical exercise to achieve enduring clinical impact. The benefit of regular physical exercise in schizophrenia as a whole and in the presence of metabolic complications in particular cannot be overstated. A recent Cochrane review has summarized the “healthful effects on both the physical and mental health and well-being of individuals with schizophrenia.”[33] Exercise aids the individual at many levels. It has a positive impact on symptom control, cognition, immunological parameters and brain protective molecules like brain derived neurotrophic factor and is directly effective in treatment of metabolic complications.[34] That exercise may have a positive stabilizing influence of all links between schizophrenia and metabolic disorders, in the absence of side-effects makes it an attractive therapeutic strategy, which is often underutilized. Yoga - as a combination of life-style modification and physical exercise also has similar beneficial potential, which was validated in a recently published systematic review.[35]

In summary, the interaction between metabolic syndrome and schizophrenia opens up investigative opportunities right from the epidemiological and clinical level to the molecular. In times to come, the common links can potentially unravel the complex etiology of these disorders. At the very least, exploration of molecular links will lead to more targeted, more selective drug targets. One may, at least theoretically, expect to find different isoforms of second messengers, which mediate dopamine and insulin action. Selective action on one, without disturbing the other signaling systems may therefore help in management of symptoms of schizophrenia without invoking the metabolic dysregulation. Until such a time, metabolic complications in schizophrenia are likely to persist as a necessary evil and hence proactive clinical assessment and intervention is of paramount significance in contemporary treatments strategies for schizophrenia.[7]