Schizophrenic Disorders: Is There an Elephant?

In the Indian parable of the blind men and the elephant, a group of blind men touch various parts of an elephant to identify it. One man feels the beast’s trunk and thinks it may be a hose. Another feels its body and thinks it is a wall. Yet another feels its tail and concludes it is snake.

This story may be interpreted as one person’s truth not being a total truth-and that multiple perspectives are required to fully understand a concept. This seems to be the growing consensus with the schizophrenia spectrum disorders. At the APA 2015 conference, the theme of multiple perspectives was evident across the pathophysiology, diagnosis, and treatment of the psychotic disorders.

[[{"type":"media","view_mode":"media_crop","fid":"38624","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_7143363786598","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3855","media_crop_rotate":"0","media_crop_scale_h":"174","media_crop_scale_w":"150","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]Schizophrenia is a highly heritable disorder, which suggests a major role for various alleles in its etiology. At the conference, Anil Malhotra, MD, discussed a recent multistage schizophrenia genome-wide association study published in the journal Nature.¹ In that study, all available schizophrenia samples with published or unpublished genome-wide association study genotypes (36,989 cases and 113,075 controls) were combined into a systematic analysis. The results were 108 conservatively defined loci that met genome-wide significance, which coded for approximately 341 different genes. The identified loci likely represented the low-hanging fruit, with larger effect sizes, and it is likely that many more loci-and therefore more functional units-exist with reduced relative impact.

What is fascinating is that when the group cross-referenced the genes in a drug target database, 20 drug targets were identified for which there are approved drugs. Calcium channel modifiers, NMDA antagonists, nicotine partial agonists, and the well-known DRD2 receptor antagonists were identified. This indicates that even viewed through a strictly genetic lens, schizophrenia is not a single disorder, but rather a spectrum-some possibly channelopathies, some glutamatergic-related, some dopamine- and glutamate-related, and possibly other variants as well.

In an associated talk, Matcheri Keshavan, MD, noted that the 341 genes could be organized into functional gene networks, consisting of immunity-related genes and ones involved in the glutamate system.

Rajiv Tandon, MD, discussed the attempt of DSM-5 to embrace the heterogeneity of schizophrenia, through the new 0-4 subscale rating across 8 dimensions: hallucinations, delusions, disorganized speech, negative symptoms, disorganized behavior, mood, motor, and cognition. It is important to consider all 8 when constructing and monitoring a treatment plan.

Henry A. Nasrallah, MD, discussed treatment by considering that at present only positive symptoms, motor and, at times, mood, are targets for intervention. He suggested a 3-pronged approach, conceptualizing biological treatment from neurodevelopmental, neurochemical, and neurodegenerative viewpoints. Neurodevelopmentally, one should encourage patients to minimize the risk of perinatal infection, such as toxoplasmosis, which has been linked to increased risk of schizophrenia.² He also recommended perinatal vitamin D, to reduce gestational diabetes risk. From a neurochemical and neurodegenerative standpoint, he recommended using atypical antipsychotics, which are associated with increased neurogenesis through neurotrophic growth factors into the hippocampus. He recommended avoiding typical antipsychotics, such as haloperidol, fluphenazine, and perphenazine, all of which are associated with neuronal apoptosis and necrosis.³ This is particularly concerning, given that preventing exacerbations of schizophrenia is thought to be important in reducing brain volume loss. Lithium and SSRIs were also mentioned as having effects associated with increased brain-derived neurotrophic factor in the brain.

The elephant parable can be interpreted as a metaphor for multiple perspectives to find total truth. Schizophrenia is now viewed as a spectrum with multiple parts to be examined by researchers. Given the above, it seems more likely that what we will find is that there is no elephant at all, but a collection of different parts, each with its own etiology and treatment.

This article was originally posted on 5/22/2015 and has since been updated.

Disclosures:

Dr Naidoo is a fourth year psychiatry resident in the Department of Psychiatry and Behavioral Neurosciences at Wayne State University in Detroit.

References:

1. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421-427.

2. Torrey EF, Yolken RH. Toxoplasma gondii and schizophrenia. Emerg Infect Dis.2003;9:1375-1380.

3. Nasrallah HA. Haloperidol is clearly neurotoxic. Should it be banned? Curr Psychiatry. 2013;12:7-8.