26th July 2016

Preventive treatment in schizophrenia:
an alternative to crisis intervention?

“My greatest fear is this brain of mine…. The worst thing imaginable is to be terrified of one’s own mind, the very matter that controls all that we are and all that we do and feel.”
Patient suffering from schizophrenia
1

Schizophrenia is an intense psychotic disorder characterized by an unending roller coaster of disorganized thinking, delusions, hallucinations, paranoia, avolition, fear, and shame.These symptoms are often resistant to medication and are associated with poor overall functioning, impaired relationships, and social withdrawal. There is therefore a need for greater clinical efficacy. 

Whilst treatment with first- and second-generation antipsychotics has been developed to alleviate symptoms characteristic of schizophrenia, the general scientific community is putting forward a new line of thought suggesting tackling the causes, pathophysiology, and course of schizophrenia before the onset of the disorder itself.2 Our understanding of the neurobiology that characterizes schizophrenia is growing, promoting the idea that early intervention could alter its course.2 Since some core symptoms of schizophrenia are shared with other disorders, course-altering strategies could be of broader therapeutic value too.2 

However, identifying clinically high-risk (CHR) patients prone to developing schizophrenia is a major challenge.3 Whilst CHR patients display several features that progressively emerge, only a minority of CHR individuals actually develop schizophrenia or another psychotic disorder.3 As 70% of mental disorders first manifest themselves before the age of 25,4 it is important to develop strategies - other than clinical observation alone - that accurately predict the risk of transition to schizophrenia with as few false positives and false negatives as possible. 

The first approach under development is based on the identification of genes and gene networks associated with a high risk of transition such as the neuregulin 1 gene.5 The second approach is based on changes in the levels of biomarkers including brain derived neurotrophic factor.6,7 The third approach analyses changes in neurotransmission, loss of grey matter in certain brain regions, and disruption of network connectivity.8-11 Finally, event-related tools are showing promise for improving psychosis prediction.12 

Clinical studies where at-risk individuals were treated with omega‑3 polyunsaturated fatty acids, second-generation antipsychotics with cognitive-behavioural therapy, and various non-pharmaceutical treatments have been conducted, in which the numbers of patients developing schizophrenia decreased.2 However, it is not yet clear whether transition is just delayed or halted permanently. Ongoing studies are focused on combination strategies to improve on single approaches. Early intervention before the onset of schizophrenia therefore offers patients huge potential benefits in terms of better clinical, social and vocational outcomes, reduced in-patient stays, and ultimately may change the trajectory from one of tragic decline to one of a chronic but manageable condition.

 

References

Ruocchio PJ. First Person Account: The Schizophrenic Inside. Schizophrenia Bulletin 1991; 17: 357-360.

Millan MJ, Andrieux A, Bartzokis G, Cadenhead K, Dazzan P, Fusar-Poli P, et al. Altering the course of schizophrenia: progress and perspectives. Nature Reviews Drug Discovery 2016 [Epub ahead of print].

Schultze-Lutter F, Michel C, Schmidt SJ, Schimmelmann BG, Maric NP, Salokangas RK, et al. EPA guidance on the early detection of clinical high risk states of psychoses. European Psychiatry 2015; 30: 405-416.

Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 2005; 62: 593-602.

Bousman CA, Yung AR, Pantelis C, Ellis JA, Chavez RA, Nelson B, et al. Effects of NRG1 and DAOA genetic variation on transition to psychosis in individuals at ultra-high risk for psychosis. Translational Psychiatry 2013; 3: e251.

Mondelli V, Cattaneo A, Belvederi Murri M, Di Forti M, Handley R, Hepgul N, et al. Stress and inflammation reduce brain-derived neurotrophic factor expression in first‑episode psychosis: a pathway to smaller hippocampal volume. Journal of Clinical Psychiatry 2011; 72: 1677-1684.

Niwa M, Jaaro-Peled H, Tankou S, Seshadri S, Hikida T, Matsumoto Y, et al. Adolescent stress-induced epigenetic control of dopaminergic neurons via glucocorticoids. Science 2013; 339: 335-339.

Kegeles LS, Abi-Dargham A, Frankle WG, Gil R, Cooper TB, Slifstein M, et al. Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Archives of General Psychiatry 2010; 67: 231-239.

Schobel SA, Chaudhury NH, Khan UA, Paniagua B, Styner MA, Asllani I, et al. Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron 2013; 78: 81-93.

Tognin S, Pettersson-Yeo W, Valli I, Hutton C, Woolley J, Allen P, et al. Using structural neuroimaging to make quantitative predictions of symptom progression in individuals at ultra-high risk for psychosis. Frontiers in Psychiatry 2014; 4: 187.

Brennan AM, Harris AW, Williams LM. Functional dysconnectivity in schizophrenia and its relationship to neural synchrony. Expert Review of Neurotherapeutics. 2013; 13: 755-765.

Bodatsch M, Brockhaus-Dumke A, Klosterkötter J, Ruhrmann S. Forecasting psychosis by event-related potentials-systematic review and specific meta-analysis. Biological Psychiatry 2015; 77: 951-958.