Proteomic Enrichment Analysis of Psychotic and Affective Disorders Reveals Common Signatures in Presynaptic Glutamatergic Signaling and Energy Metabolism

Background:

Although genetic studies suggest an overlap in risk alleles across the major psychiatric disorders, disease signatures reflecting overlapping symptoms have not been found. Profiling studies have identified candidate protein markers associated with specific disorders of the psychoaffective spectrum, but this has always been done in a selective fashion without accounting for the entire proteome composition of the system under investigation.

Methods:

Employing an orthogonal system-based proteomic enrichment approach based on label-free liquid chromatography mass spectrometry, we analyzed anterior prefrontal human post-mortem brain tissue of patients affected by schizophrenia (n = 23), bipolar disorder (n = 23), major depressive disorder with (n = 12) and without psychotic features (n = 11), and healthy controls (n = 23). Labeled selected reaction monitoring (SRM) was used to validate these findings on a pathway level. Independent in silico analyses of biological annotations revealed common pathways across the diseases, associated with presynaptic glutamatergic neurotransmission and energy metabolism. We validated the proteomic findings using SRM and confirmed that there were no effects of post-mortem confounders.

Results:

Schizophrenia and affective psychosis were linked to a hypoglutamatergic state and hypofunction of energy metabolism, while bipolar disorder and major depressive disorder were linked to a hyperglutamatergic state and hyperfunction of energy metabolism.

Conclusions:

These findings support recent investigations, which have focused on the therapeutic potential of glutamatergic modulation in psychotic and affective disorders. We suggest a disease model in which disturbances of the glutamatergic system and ensuing adaptations of neuronal energy metabolism are linked to distinct psychiatric symptom dimensions, delivering novel evidence for targeted treatment approaches.     

The role of proteomics in depression research

Depression is a severe neuropsychiatric disorder affecting approximately 10% of the world population. Despite this, the molecular mechanisms underlying the disorder are still not understood. Novel technologies such as proteomic-based platforms are beginning to offer new insights into this devastating illness, beyond those provided by the standard targeted methodologies. Here, we will show the potential of proteome analyses as a tool to elucidate the pathophysiological mechanisms of depression as well as the discovery of potential diagnostic, therapeutic and disease course biomarkers.     

Metabonomic studies of schizophrenia and psychotropic medications: focus on alterations in CNS energy homeostasis

Schizophrenia is a severe neuropsychiatric disorder with a poorly understood etiology and progression. We and other research groups have found that energy metabolic pathways in the CNS are perturbed in many subjects with this disorder. Antipsychotic drugs that generally target neurotransmission are currently used for clinical management of the disorder, although these can also have marked effects on energy metabolism in the CNS and periphery. Recent proteomic and metabonomic studies have shown that molecular pathways associated with brain energy metabolism are altered in both the disorder and by antipsychotic treatments. This review focuses on discussion of these molecular alterations. Increased knowledge in this area could facilitate biomarker identification and drug discovery based on improving brain energy metabolism in this debilitating disorder.     

Metronidazole Induced Encephalopathy in a Patient with Brain Abscess

Metronidazole is commonly used for brain abscess but is not well known for its neurotoxic complications. Metronidazole-induced encephalopathy (MIEP) is toxic encephalopathy associated with the use of metronidazole. We experienced a case of brain abscess which developed reversible severe MIEP during treatment period. Although MIEP occurs in typical locations, it is not easy to differentiate from other conditions such as cerebral infarction, demyelinating diseases and metabolic diseases. Neurosurgeons should be aware that severe MIEP can occur during the use of metronidazole though it is not common.     

Myasthenia Gravis,Schizophrenia, and Colorectal Cancer in A Patient: Long-Term Follow-Up with Medication Complexity

In a case of 46-year-old woman suffering from schizophrenia for over 20 years, she experienced frequent episodes of dyspnea and confirmed as superimposed with myasthenia gravis (MG). Throughout the seven-year follow-up period, after diagnosed as MG, she has been hospitalized 6 times and also diagnosed as colorectal cancer. Authors experienced various conditions associated with untoward effects of medication for myasthenia, schizophrenia, and colorectal cancer. Therefore, authors reported considerations for the pharmacotherapy of schizophrenia with myasthenia gravis.