Investigation of TSPO variants in schizophrenia and antipsychotic treatment outcomes

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From: Pharmacogenomics(Vol. 16, Issue 1)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 10,835 words
Lexile Measure: 1870L

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Author(s): Jennie G Pouget aff1 aff2 aff3 , Vanessa F Gonçalves aff1 aff3 , Erika L Nurmi aff4 , Christopher P Laughlin aff4 , Karyn S Mallya aff4 , James T McCracken aff4 , Michael G Aman aff5 , Christopher J McDougle aff6 , Lawrence Scahill aff7 , Virginia L Misener aff1 , Arun K Tiwari aff1 , Clement C Zai aff1 aff3 , Eva J Brandl aff1 aff8 , Daniel Felsky aff1 aff2 aff3 , Amy Q Leung aff1 , Jeffrey A Lieberman aff9 aff10 , Herbert Y Meltzer aff11 , Steven G Potkin aff12 , Charlotte Niedling aff13 , Werner Steimer aff13 , Stefan Leucht aff14 , Jo Knight aff1 aff2 aff3 aff15 , Daniel J Müller [*] aff1 aff2 aff3 aff16 , James L Kennedy aff1 aff2 aff3

Keywords:

adenine nucleotide translocator; antipsychotic; genetics; mitochondria; peripheral benzodiazepine receptor; pharmacogenomics; schizophrenia; SLC25A4; TSPO; translocator protein-18 kDa; weight gain

Schizophrenia is a devastating mental illness characterized by positive symptoms (exaggerations of normal perceptions, e.g., delusions and hallucinations) and negative symptoms (deficits in cognitive or emotional processes, e.g., emotional blunting and lack of motivation). Antipsychotic drugs, the mainstay treatment for schizophrenia, significantly reduce positive symptoms but are less effective in treating negative symptoms [ 1 ]. While antipsychotic treatment leads to successful remission for many patients, there is large interindividual variability in both its efficacy and adverse effects. Up to 30% of patients with schizophrenia do not respond to antipsychotic treatment, and 5-20% experience adverse effects that cause them to discontinue therapy [2 ]. Weight gain is a particularly concerning side effect, especially for second-generation antipsychotics (SGAs), with up to 30% of patients gaining 7% or more of their initial body weight over the course of treatment [ 3 ].

Genetics are a major contributing factor to interindividual variability in both liability to schizophrenia and antipsychotic treatment outcomes ( h 2 ˜ 0.80) [4-7 ]. The most recent genome-wide association study (GWAS) of schizophrenia included over 35,000 cases, and identified 108 genomic regions robustly associated with the disease [8 ]. While representing a major advance in schizophrenia research, the collection of this large GWAS sample has come at the cost of detailed phenotypes. Schizophrenia is an umbrella diagnosis, capturing a heterogeneous group of patients, and genetic analysis of specific clinical characteristics therefore has the potential to improve our understanding of the disease [ 9 ]. Furthermore, pharmacogenetic analysis of antipsychotic treatment outcomes may accelerate the discovery of new drug targets and the implementation of a personalized approach to treatment selection. Thus, hypothesis-driven genetic studies in rigorously phenotyped samples represent a complementary approach to the large-scale GWAS that have recently been conducted in schizophrenia.

TSPO has emerged as a potential therapeutic target in anxiety disorders [ 10 ], Alzheimer's disease [11 ] and multiple sclerosis [12 ]. Previously known as the peripheral benzodiazepine receptor for its discovery as a secondary receptor for diazepam [13 ], TSPO is a highly conserved and ubiquitous transmembrane protein localized to the outer mitochondrial membrane [14 ], where it appears to form a multiunit complex with voltage-dependent anion channels (including that encoded by VDAC1 ) and adenine nucleotide translocators (including that encoded by SLC25A4...

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Gale Document Number: GALE|A412067383