Team FUD has in this post focused on two papers investigating insulin and neuropathological diseases. The first paper is reviewed by Celine Gerber, and the second paper by Ida Marie Brandt. Enjoy!

Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway

  • RR Girgis et al.

What is Schizophrenia?

Schizophrenia is a mental illness marked by chronic debilitating positive and negative symptoms affecting how the individual thinks feels and behaves. Excessive activity of Dopamine D2 receptor is an apparent factor in the development of Schizophrenia. In treating schizophrenia, antipsychotic drugs are administered. Antipsychotic drugs are differentiated as first generation antipsychotic’s and second generation antipsychotics.

What are the differences between first and second generation antipsychotics?

There are notable differences in both first generation and second generation antipsychotics one difference being the side effects. There is a high affinity of metabolic side effects among consumers of the second generation antipsychotics whereas we see more Extrapyramidal symptoms (EPS) in First generation. Metabolic symptoms include weight gain and an increase in blood glucose and insulin levels. More interesting is that the second generation antipsychotics have shown to be most effective in treating symptoms of schizophrenia. Clozapine, a second generation antipsychotic which is considered to be the most effective antipsychotic, is high in metabolic disturbance, however, there are little to no EPS side effects. This relationship begs the question as to why effective reduction of schizophrenic symptoms coincides with metabolic disturbances.

Insulin Signaling Cascade

Potential mechanisms involved in schizophrenia include PI3k and AKI due to the insulin signaling cascade. It is possible that Insulin Signaling Growth Factor (IGF) abnormalities make an individual more susceptible to the development of Schizophrenia. IGF effects are mediated by the insulin signaling cascade that leads to the activation of AKT and PKC which are linked to the glucose metabolism and transport effects of insulin. Effects in these pathways would make sense because glucose and insulin are required for metabolic mechanisms that control orexogenic and anorexogenic behavior and so creates implications in weight gain. On the other hand it has also been observed that PI3k and AKT have been implicated in the development of schizophrenia.

Insulin signaling in schizophrenia

Dopamine is also a major role in the development of schizophrenia. Recently, involvement of AKT (previously mentioned as involved with the insulin signaling cascade) and GSK (a substrate of AKT) has been linked to Dopamine thereby creating metabolic implications of the link between schizophrenia and insulin. Inhibition of GSK-3 in mice also inhibits Dopamine dependent behaviors. There is also evidence of a link between dopamine in AKT. It has been found that the binding of Dopamine to D2 receptors leads to the formation of b-arrestin 2, Akt and protein phosphatase 2A and facilitating the phosphorylation of AKT (see figure below).

Why is this important?

These results point to a connection between the body’s metabolism (specifically the insulin signaling cascade) and the development of schizophrenia. These results further our understanding of the abnormalities that lead to the development of schizophrenia and in the future may lead to the development of more efficient antipsychotic medication.

Crosstalk between metabolic and neuropsychiatric disorders

  • Oksana Kaidanovich-Beilin et al.

The high co-occurrence of metabolic disturbances and neuropsychiatric disorders suggests that they share pathophysiological mechanisms. Insulin is typically associated with its role in energy homeostasis, but it is now acknowledged as a pleiotropic peptide with critical importance in neurotrophism, neuromodulation, and neuroplasticity as well. The role of insulin in normal and abnormal brain functions is reviewed in the paper.

Convergent evidence suggests that abnormal insulin signaling mediates alterations in neuronal integrity and function because of interplay between insulin and central reward networks, stress, and neuroinflammation. For example there is a high co-occurrence of depression and diabetes, and diabetes and insanity are co-expressed in families. Metabolic disturbances such as insulin resistance, type II diabetes mellitus, and obesity are implicated in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, and in psychiatric disorders such as schizophrenia and bipolar disorder. There is convergent evidence that indicate that the relationship between congenital neurodegenerative disorders and metabolic complications might be causative.

Humoral factors such as hormones and cytokines, which conduct communication between the brain and peripheral organs, are suggested as important in the nexus of pathophysiological changes in brain functions and metabolic status.

Stress has also been implicated in psychiatric disorders such as addiction, and overactivation of the hypothalamic-pituitary-adrenal axis results in overexpression of corticotrophin-releasing hormone and thereby increased food intake, obesity, and insulin resistance, as well as anxiety and impaired learning.

Immunomodulating agents such as cytokines are increased during inflammatory processes, both in the brain and peripheral organs. Chronic inflammation is an important component in the pathogenesis of both metabolic disturbances and neuropsychiatric disorders. Patients with Parkinson’s disease and Alzheimer’s disease have inflammatory processes such as activated astrocytes and microglia, as well as inflammatory cytokines. The synthesis of neurotransmitters are affected by cytokines, which thereby regulate release and reuptake of monoamines, linking them to depression. This is underscored by elevated cytokine levels in subjects with mood disorders.

Insulin signaling in the brain is essential in regulation of glucose metabolism and energy homeostasis in the whole body. Contrary to the anabolic effect of insulin in the peripheral tissues, insulin has catabolic effects in the brain. In addition to its regulation of feeding behavior, insulin regulates neurons in the dopamine system, affecting the reward circuits and thereby motivation, reinforcing properties of food. Furthermore insulin is key in regulation of normal emotional and cognitive brain functions, and contributes to memory and learning.

Metabolic and neuropsychiatric disorders therefore seem to share a common pathophysiological nexus, including effectors such as energy metabolism, inflammation, insulin resistance, and corticosteroid signaling.

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